WO2021111311A2 - Novel adamantane derivatives as inhibitors of focal adhesion kinase - Google Patents

Novel adamantane derivatives as inhibitors of focal adhesion kinase Download PDF

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Publication number
WO2021111311A2
WO2021111311A2 PCT/IB2020/061350 IB2020061350W WO2021111311A2 WO 2021111311 A2 WO2021111311 A2 WO 2021111311A2 IB 2020061350 W IB2020061350 W IB 2020061350W WO 2021111311 A2 WO2021111311 A2 WO 2021111311A2
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Prior art keywords
amino
cancer
trifluoromethyl
pyrimidin
adamantane
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PCT/IB2020/061350
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French (fr)
Korean (ko)
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WO2021111311A3 (en
Inventor
기민효
권호석
이영훈
송은선
박용빈
이국화
조형민
안순길
홍성표
김성혜
Original Assignee
삼진제약주식회사
인천대학교 산학협력단
주식회사 바미켐
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Application filed by 삼진제약주식회사, 인천대학교 산학협력단, 주식회사 바미켐 filed Critical 삼진제약주식회사
Priority to CN202080082764.3A priority Critical patent/CN114929675B/en
Priority to JP2022532125A priority patent/JP7390487B2/en
Priority to EP20895884.3A priority patent/EP4074697A4/en
Priority to US17/782,117 priority patent/US20230049557A1/en
Publication of WO2021111311A2 publication Critical patent/WO2021111311A2/en
Publication of WO2021111311A3 publication Critical patent/WO2021111311A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel adamantane derivative as a local adhesion kinase inhibitor, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or solvate thereof, and a pharmaceutical composition comprising the same.
  • Cancer is known as the most feared incurable disease for which modern medicine has not yet developed an appropriate treatment method despite the increasing incidence of cancer as a disease with high mortality worldwide.
  • anticancer drugs mainly inhibit the cell growth mechanism or are related to the mechanism of inducing apoptosis, and have side effects such as cytotoxicity by affecting not only cancer cells but also normal cells.
  • unique characteristics of cancer cells have been revealed, and many new molecular-level targets involved in these characteristics have been discovered through genome sequencing. Development is actively taking place.
  • signal transduction systems existing in cells are organically linked to each other to form complex mechanisms, thereby controlling cell proliferation, growth, metastasis, and death.
  • protein tyrosine kinases play an important role in cellular regulatory functions. Many diseases are associated with abnormal cellular responses triggered by protein tyrosine kinases. These diseases include autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, viral diseases and hormone-related diseases. Since a lot of abnormal expression and mutation are observed, many studies are being made in pharmaceutical chemistry to develop an effective protein tyrosine kinase inhibitor as an anticancer treatment.
  • FAM Focal adhesion kinase
  • PTK2 is a protein encoded by the PTK2 gene, which is a non-receptor tyrosine kinase present in the cytoplasm and receives signals from integrin and growth factor receptors for cell growth, proliferation, adhesion, migration, invasion and It is known to play an important role in the regulation of self-reproduction of cancer stem cells.
  • FAK is regulated and activated through autophosphorylation of Y397, and binds to self-phosphorylated Y397 through the SH2 domain of Src protein, which is another tyrosine kinase, and Src protein phosphorylates Y925 of FAK, attracting adapter protein Grb2, It induces activation of the ras and MAP kinase pathways involved in regulating cell proliferation.
  • signal transduction via FAK is very tightly regulated, but in cells transformed into tumors, FAK is overexpressed and activated, causing various characteristics of malignant tumors.
  • FAK protein and mRNA were found to be overexpressed in various solid cancers such as breast cancer, colorectal cancer, lung cancer, ovarian cancer, prostate cancer, as well as blood cancers such as acute myeloid leukemia, and phosphorylated FAK showing activity increased in malignant tissues than in normal tissues
  • various solid cancers such as breast cancer, colorectal cancer, lung cancer, ovarian cancer, prostate cancer, as well as blood cancers such as acute myeloid leukemia, and phosphorylated FAK showing activity increased in malignant tissues than in normal tissues
  • proline-rich tyrosine kinase 2 (PYK2), the only subtype of FAK, is most widely distributed in neurons, and has recently been valued as a molecular target for the development of anticancer drugs such as small cell lung cancer, prostate cancer, hepatocellular cancer, and glioma.
  • anticancer drugs such as small cell lung cancer, prostate cancer, hepatocellular cancer, and glioma.
  • TAE226 is Taxane-sensitive cell 1 ine (HeyA8, SK0V3ip) and Taxane-resistant cell.
  • Non-Patent Document 1 Cancer Res. 2007, 67: 10976-10983
  • Non-Patent Document 2 Expert Opin. Investing. Drugs, 2010, 19:777-788
  • An object of the present invention is to solve the above problems, and as a local adhesion kinase inhibitor, a novel adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof is provided.
  • Another object of the present invention is to provide a pharmaceutical composition comprising a novel adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof as an active ingredient as the local adhesion kinase inhibitor. .
  • Another object of the present invention is a novel adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer, a hydrate or a solvate thereof, as an active ingredient as the local adhesion kinase inhibitor.
  • Another object of the present invention is to provide a novel topical adhesion kinase inhibitor. 2021/111311 - 01/162020/061350 of adamantane derivative, its pharmaceutically acceptable salt, its stereoisomer, its hydrate or solvate comprising administering to an individual a therapeutically effective amount of a related disease To provide a method of prevention or treatment.
  • Another object of the present invention is To provide the use of a novel adamantane derivative, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate or a solvate thereof as the local adhesion kinase inhibitor for the prevention or treatment of related diseases.
  • Another object of the present invention is To provide the use of a novel adamantane derivative, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate or a solvate thereof as the local adhesion kinase inhibitor for the preparation of a medicament for the prevention or treatment of related diseases.
  • a novel adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof as a local adhesion kinase inhibitor of the present invention is represented by the following formula (1).
  • 3 ⁇ 4 and 3 ⁇ 4 are each independently -1 () heterocycloalkylene, 3 ⁇ 4- 1 () cycloalkylene, 3 ⁇ 4- 16 arylene or 0 4 , heteroarylene;
  • 3 ⁇ 4 and 3 ⁇ 4 are each independently II or -10 alkyl; Myo 7 is _ 0? 3 or a halogen atom; kill; ⁇ II, I) and (1 are each independently 0 or 1.
  • 3 ⁇ 4 and 3 ⁇ 4 of Formula 1 are each independently, 2021/111311 ?01/162020/061350 independently
  • the compound represented by Formula 1 may be a compound represented by Formula 2 below.
  • 3 ⁇ 4 is II or -10 alkyl; kill; II, I) and (1 are each independently 0 or 1.
  • the novel adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer, a hydrate or a solvate thereof selectively inhibits the activity of FAK and Pyk2 (FAK2) At the same time, it exhibits an action effect that does not inhibit insulin receptor (Ins-R) activity.
  • the adamantane derivative, its pharmaceutically acceptable salt, its stereoisomer, its hydrate or solvate according to the present invention inhibits the abnormal activity of FAK, thereby inhibiting the abnormal activity of FAK Abnormal cell growth disease induced by inhibition It can be usefully used for prevention and treatment.
  • FIG. 1 shows the results of a 3D spheroid assay for analyzing the growth inhibition of cancer cell spheroids of the adamantane derivative compound of the present invention.
  • 2 is a microscopic analysis result for analyzing the 3D invasion inhibition degree of the human triple-negative breast cancer cell line MDA-MB-231 of the adamantane derivative compound of the present invention.
  • 3 is a result of analyzing the 3D invasion inhibition degree of the adamantane derivative compound of the present invention, MDA-MB-231, a human triple-negative breast cancer cell line.
  • 4 is a result of analyzing the degree of tumor growth inhibition of the adamantane derivative compound of the present invention in a triple-negative breast cancer xenograft mouse model. 2021/111311 ?01/162020/061350
  • substitution or “substituted with” depends on the permissible value of the atom and substituent in which the substitution is substituted, and a compound that is stable by substitution, for example, a compound that is not naturally modified by rearrangement, cyclization, removal, etc. It is defined as including an implicit condition that induces
  • single bond refers to a case in which atoms or groups of atoms adjacent to Li or L2 are directly bonded to each other.
  • alkyl refers to a linear (or straight chain, l inear) saturated hydrocarbon group or a branched (or branched, branched) saturated hydrocarbon group, methyl, ethyl, n_ propyl, isopropyl, n-butyl , including, but not limited to, sec-butyl, isobutyl, tert-butyl, n_pentyl, n_nuclear, n_heptyl, and the like.
  • alkylene refers to a divalent functional group derived from alkyl as defined above.
  • alkenyl refers to an unsaturated hydrocarbon group containing at least one double bond between carbons
  • alkynyl refers to an unsaturated hydrocarbon group containing at least one triple bond between carbons
  • alkenylene refers to a divalent functional group derived from alkenyl as defined above
  • alkynylene refers to a divalent functional group derived from alkynyl as defined above.
  • halogen atom means F, Cl , Br or I.
  • aryl also includes a monocyclic aromatic or polycyclic aromatic and a monocyclic or polycyclic aromatic structure in which a saturated hydrocarbon ring is fused.
  • Aryl is a phenyl group, biphenyl, 2021/111311 ?01/162020/061350 Naphthalenyl, tetrahydronaphthalenyl, anthracenyl, phenanthrenyl, pyrenyl, etc., but are not limited thereto.
  • heteroaryl refers to a monocyclic or polycyclic heterocyclic ring in which at least one carbon atom in the aryl group is substituted with nitrogen), oxygen (0), or sulfur).
  • Heteroaryl is pyridinyl, thiophenyl, triazolyl, tetrazolyl, benzodioxolyl, benzothiazolyl, benzothiophenyl, quinolinyl, indolyl, isoindolyl, benzofuranyl, benzopyrrolyl, furanyl, p Rollyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, carbazolyl, benzoxazolyl, benzodioxazolyl, including benzodioxinyl, benzoimidazolyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, purinyl, indolizinyl, chromanyl, chromenyl,
  • Cycloalkyl includes, but is not limited to, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydronaphthalenyl, adamantyl, and the like.
  • heterocycloalkyl is a saturated monocyclic and polycyclic hetero ring containing 1 to 4 heteroatoms independently selected from nitrogen), oxygen (0) and sulfur), or two or more rings are at least one pair It refers to a ring structure in which carbon atoms are shared.
  • Heterocycloalkyl is oxiranyl, oxetanyl, morpholinyl, 2021/111311 ?01/162020/061350 Thietanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, 6 - azaby cyclo[3.2.1]octanyl, and the like, but are not limited thereto.
  • cycloalkylene refers to a divalent functional group derived from cycloalkyl
  • heterocycloalkylene refers to a divalent functional group derived from heterocycloalkyl.
  • the adamantane derivative represented by Formula 1 according to the present invention may be any one compound selected from the group consisting of compounds shown in the following table. 2021/111311 1 ⁇ (:1 ⁇ 2020/061350
  • stereoisomer includes diastereomers and optical isomers, and optical isomers include not only enantiomers, but also mixtures of enantiomers and racemates.
  • pharmaceutically acceptable salt refers to a salt commonly used in the pharmaceutical industry, for example, calcium, potassium, sodium and magnesium, etc.
  • inorganic ions prepared salts, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid, hydroiodic acid and sulfuric acid; Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid acid, ascorbic acid, an organic acid salt prepared with carbonic acid and vanillic acid; sulfonic acid salts prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, ]3-toluenesulfonic acid and naphthalenesulfonic acid; Amino acid salts prepared from glycine, argin
  • the 'hydrate' of the present invention is an adamantane derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof and water, which are bound by a non-covalent intermolecular force, and includes a stoichiometric or non-stoichiometric amount of water.
  • the hydrate may contain water in a ratio of about 0.25 mole to about 10 moles based on 1 mole of the active ingredient, and more specifically, about 0.5 mole, about 1 mole, about 1.5 mole, about 2 mole, about 2.5 moles, about 3 moles, about 5 moles, etc. may be included.
  • the 'solvate' of the present invention is an adamantane derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof and a solvent other than water combined by an intermolecular force, and the solvent is included in a stoichiometric or non-stoichiometric amount can do.
  • the 2021/111311 - 01/162020/061350 The solvate may contain solvent molecules in a ratio of about 0.25 to about 10 moles based on 1 mole of the active ingredient, and more specifically, about 0.5 moles, about 1 moles, about 1.5 moles , about 2 moles, about 2.5 moles, about 3 moles, about 5 moles, etc. may be included.
  • inhibitor refers to a compound that blocks or reduces the activity of an enzyme. Inhibitors can bind reversibly or irreversibly, therefore, the term includes compounds that kill the substrate of the enzyme. Inhibitors may modify one or more sites on or near the enzyme active site, or may cause a conformational change elsewhere on the enzyme
  • Composition comprising an adamantane derivative compound, its use, and a treatment method using the same
  • a pharmaceutical composition comprising an adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof as an active ingredient.
  • the present invention provides an adamantane derivative, a pharmaceutically acceptable salt thereof , containing its stereoisomer, its hydrate or solvate as an active ingredient,
  • a pharmaceutical composition for preventing or treating an activity-related disease is provided.
  • the adamantane derivative of the present invention a stereoisomer or a pharmaceutically acceptable salt thereof and ? It is possible to inhibit the activity of at least one of 2 and 2) in urine.
  • Abnormalities induced by abnormal activity 2021/111311 ?01/162020/061350 Cell growth disease, autoimmune disease, inflammatory disease, bone disease, metabolic disease, neurological and neurodegenerative disease, cancer, cardiovascular disease, allergy and asthma, Alzheimer's disease, viral disease and hormone-related It may be at least one selected from the group consisting of diseases, preferably stomach cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, uterine cancer, cervical cancer, ovarian cancer, both It may be any one selected from the group consisting of solid cancers including cervical cancer, thyroid cancer, parathyroid cancer, kidney cancer, prostate cancer, urethral cancer, bladder cancer, mesothelioma, and blood cancer including leukemia, multiple myeloma, lymph
  • the abnormal cell growth disease induced by the abnormal activity of FAK may be any one selected from the group consisting of invasive and metastatic triple-negative breast cancer, colorectal cancer, lung cancer and malignant mesothelioma. Besides symptoms or diseases associated with abnormal function.
  • the adamantane derivative of the present invention a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof for the prevention or treatment of a disease.
  • the present invention provides a method for preventing or treating a disease related to FAK activity, comprising administering to an individual a therapeutically effective amount of an adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof provides
  • prevention refers to any action that suppresses or delays the onset of an activity-related disease by administration of the compound according to the present invention.
  • treatment refers to the administration of the compound according to the present invention. 2021/111311 ?01/162020/061350 Refers to any action in which symptoms for an active-related disease are improved or changed to a beneficial effect.
  • the present invention comprises administering to an individual an adamantane derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof
  • a method for inhibiting the activity of of the present invention is by administering an adamantane derivative compound, a pharmaceutically acceptable salt thereof, a stereoisomer, a hydrate or a solvate thereof, not only to treat the disease itself before the onset of symptoms, but also to treat the symptoms It also includes inhibiting or avoiding.
  • the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition ( 11 11 ), and the route through which the active ingredient is administered.
  • the method for preventing or treating FAK activity-related diseases of the present invention is an adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof together with an additional active agent that is helpful in the treatment of diseases. It may further include administration of a pharmaceutically effective amount, and the additional active agent may exhibit a synergistic or auxiliary effect together with an adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof. .
  • Adamantane derivatives, pharmaceutically acceptable salts thereof, stereoisomers thereof, and adamantane derivatives for the preparation of drugs for the prevention or treatment of activity-related diseases It is intended to provide the use of the hydrate or solvate.
  • An adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof for the manufacture of a drug may be mixed with an acceptable adjuvant, a diluent, a carrier, etc., as a complex formulation together with other active agents may be formulated to have a synergistic action of the active ingredients.
  • the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is commonly used in the formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose , polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, etc., but is not limited thereto.
  • it may further include a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, etc.
  • the pharmaceutical composition of the present invention is cell signal transduction inhibitors (cell signal transduct ion inhibitors), mitosis inhibitors (mitosis inhibitors), alkylating agents (alkylating agents), metabolic antagonists (ant imetabol items), antibiotics (ant ibiot ics) ) , growth factor inhibitors , cell cycle inhibitors , topoisomerase inhibitors , biological reaction modi fiers , anti hormonal agents) , anti androgens , cell differentiation/proliferation/survival inhibitors (cell di fferent iat ion/prol ferat ion/survival inhibitors) , U apoptosis inducer) may additionally include a drug selected from the group consisting of, and in the case of formulating the pharmaceutical composition of the present invention, it may be combined or combined with the additionally included drug.
  • the pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or locally applied) according to a desired method, and the dosage may vary depending on the patient's condition and weight, and disease. Although it varies depending on the degree, drug form, administration route and time, it may be appropriately selected by those skilled in the art.
  • the pharmaceutical composition of the present invention is administered in a therapeutically effective amount.
  • therapeutically effective amount means an amount that is moderate to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type, severity, and drug of the patient.
  • composition according to the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple. It is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects in consideration of all of the above factors, which can be easily determined by those skilled in the art.
  • the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, weight, absorption of the active ingredient in the body, inactivation rate and excretion rate, disease type, and drugs used in combination weight 1 0.001 to 160 1 per sugar, preferably 0.01 to 100 Or administered every other day, or 1 to 3 times a day 2021/111311 ?01/162020/061350 Can be administered in divided doses.
  • the dosage is not intended to limit the scope of the present invention in any way.
  • “individual” means a subject that should be prevented or treated for disease, and more specifically, it may refer to mammals such as humans, monkeys, mice, etc. 6), dogs, cats, horses, cattle, etc.
  • the present invention is not limited thereto.
  • the terms and abbreviations used herein have their original meanings unless otherwise defined.
  • examples will be described in detail. However, the following examples are merely illustrative of the contents of the present invention, and the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.
  • Step 1 Preparation of ( ⁇ )-4-((3-methoxy-4-nitrophenyl)amino)adamantan-1-ol ⁇ ⁇ 3 « 4-aminoadamantan- 1-ol, 4-fluoro-2 -methoxy- 1-nitrobenzene, potassium carbonate, and dimethyl sulfoxide were stirred well and heated to 1201 for 5 hours. After cooling to room temperature and stirring well, water was added to the reaction solution to precipitate, and the precipitated solid was obtained by filtration. The obtained solid was purified by column chromatography to obtain the title compound.
  • Step 2 Preparation of ( ⁇ 3 ⁇ 475)-4-((4-amino-3-methoxyphenyl)amino)adamantan-1-ol After dissolving the ( ⁇ / « ⁇ -((K-methoxy-gan-nitrophenyl)amino)adamantan-1-ol prepared in step 1 in ethanol, 10% palladium/carbon catalyst was added thereto, and under hydrogen pressure Stirred for 15 hours. After completion of the reaction, filtered through celite 2021/111311 1 ⁇ (:1 ⁇ 2020/061350 The filtrate was concentrated under reduced pressure and used directly in the next step without further purification.
  • 1,2 -dichloroethane and 2,4-dichloro-5-(trifluoromethyl)pyrimidine was dissolved in a mixed solvent (1:1), zinc dichloride was added, and the mixture was stirred at room temperature for 30 minutes. After cooling to 01, ( ⁇ 5) -4-((4-amino-3-methoxyphenyl)amino)adamantan-1-ol prepared in step 2 was mixed with 1,2-dichloroethane It was dissolved in a butanol mixed solvent (1:1) and slowly added. After stirring at 01 for 1 hour, diisopropylamine was added and the mixture was stirred at room temperature for 15 hours. Ice water was poured into the reaction solution, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain the title compound.
  • Step 1 Preparation of ⁇ (3-methoxy-4-nitrophenyl)adamantan-2-amine
  • step 1 of Example 1 ⁇ 3 « 4 -Adamantane-2- instead of 4-aminoadamantane- 1-ol 2021/111311 -01/162020/061350
  • the title compound was synthesized in the same manner as in Example 1 using the amine.
  • Step 2 Preparation of ⁇ (adamantan-2-yl)- 3 -methoxybenzene- 1,4-diamine
  • step 2 of Example 1 ( ⁇ / ⁇ « ⁇ -((k-methoxy-gan-nitrophenyl)amino)adamantan-1-ol in place of ⁇ (3-methoxy-4-nitrophenyl) )
  • the title compound was synthesized in the same manner as in Example 1 using adamantane_ 2-amine.
  • Example 3 2-((2-((4-(4-(adamantane-2-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-(trifluoro Preparation of methyl)pyrimidin-4-yl)amino)-produced 3-dimethylbenzamide (Compound 3) 2021/111311 -01/162020/061350
  • step 1 of Example 1 the title compound was synthesized in the same manner as in Example 1 using piperazine instead of ⁇ 3 « 4-aminoadamantan-1-ol.
  • Step 2 Preparation of 1-(adamantan-2-yl)- 4-(3-methoxy-4-nitrophenyl)piperazine 1-(3-methoxy-4-nitrophenyl)piperazine, adamantane_2-one, triacetoxysodium borohydride, tetrahydrofuran, and acetic acid prepared in step 1 were heated at room temperature for 15 hours. stirred for a while. Ice water was poured into the reaction solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain the title compound.
  • Step 3 Preparation of 4-(4-(adamantan-2-yl)piperazin-1-yl)-2-methoxyaniline
  • step 2 of Example 1 (/ ⁇ ⁇ -(-methoxy-gan-nitrophenyl)amino)adamantan-1-ol instead of 1-(adamantan-2-yl)-4-(
  • the title compound was synthesized in the same manner as in Example 1 using 3-methoxy-4-nitrophenyl)piperazine.
  • Step 4 ⁇ (4-(4-(adamantan-2-yl)piperazin- 1-yl)-2 -methoxyphenyl-4 -chloro_ Preparation of 5-(trifluoromethyl)pyrimidin-2-amine
  • 4-(4-(adamantan-2-yl)piperazine- instead of ( «--((liver-amino-3_methoxyphenyl)amino)adamantan-1-ol) 1-yl)-
  • the title compound was synthesized in the same manner as in Example 1 using 2-methoxyaniline.
  • Step 5 2-((2-((4-(4-(adamantan-2-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-(trifluoromethyl )Pyrimidin-4-yl)amino)- ⁇
  • Step 5 2-((2-((4-(4-(adamantan-2-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-(trifluoromethyl )Pyrimidin-4-yl)amino)- ⁇
  • Step 5 2-((2-(4-(4-(4-(4-(adamantan-2-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-(trifluoromethyl )Pyrimidin-4-yl)amino)- ⁇
  • Step 1 Preparation of ( ⁇ )-4-(4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)adamantan-1-ol
  • step 2 of Example 3 the title compound was synthesized in the same manner as in Example 3 using 5-hydroxyadamantan-2-one instead of adamantan-2-one.
  • step 2 of Example 1 ( ⁇ / ⁇ « ⁇ -((k-methoxy-gan-nitrophenyl)amino)adamantan-1-ol instead of ( ⁇ )-4-(4-(3-)
  • the title compound was synthesized in the same manner as in Example 1 using methoxy-4-nitrophenyl)piperazin-1-yl)adamantan-1-ol.
  • Step 3 ( ⁇ )-4-(4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine- 1-day) Preparation of adamantane-1-ol
  • step 3 of Example 1 ( «--((liver-amino-3_ methoxyphenyl)amino)adamantan-1-ol instead of ( ⁇ )-4-(4-(4-amino-3-methyl)
  • the title compound was synthesized in the same manner as in Example 1 using oxyphenyl)piperazin-1-yl)adamantan-1-ol.
  • step 2 of Example 3 the title compound was synthesized in the same manner as in Example 3 using 5-hydroxyadamantan-2-one instead of adamantan-2-one.
  • Step 2 Preparation of (5)-4-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)adamantan-1-ol
  • step 2 of Example 1 ⁇ /?50-4-((3-methoxy-4-nitrophenyl)amino)adamantan-1-ol instead of (5)-4-(4-(3) -Methoxy-4-nitrophenyl)piperazin-1-yl)adamantan-1-ol using the same as in Example 1
  • the title compound was synthesized by the method 2021/111311 -01/162020/061350.
  • Step 3 ( )-4-(4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1 -Japanese) Preparation of adamantane- 1-ol
  • step 3 of Example 1 «--((liver-amino-3_ methoxyphenyl)amino)adamantan-1-ol instead of ( 5 )-4-(4-(4-amino-3-methyl
  • the title compound was synthesized in the same manner as in Example 1 using oxyphenyl)piperazin-1-yl)adamantan-1-ol.
  • Step 4 2-((2-((4-(4-((5)-5-hydroxyadamantan-2-yl)piperazin-1_yl)-2 -methoxyphenyl)amino)- Preparation of 5-(trifluoromethyl)pyrimidin-4-yl)amino)- ⁇ 3-dimethylbenzamide
  • step 4 of Example 1 ( ⁇ )-4-((4-((4-chloro-5-)
  • Step 1 Preparation of 4-((3-methoxy-4-nitrophenyl)amino)piperidine-1-carboxylic acid ⁇ /-butyl
  • step 1 of Example 1 the title compound was synthesized in the same manner as in Example 1 using ' ⁇ 3 « 4-aminoadamantan-1-ol instead of 4-aminopiperidine-1-carboxylic acid ⁇ /-butyl. did. 2021/111311 1 ⁇ (:1 ⁇ 2020/061350
  • Step 2 Preparation of ⁇ (3-methoxy-4-nitrophenyl)piperidin-4-amine 4-((3-Methoxy-4-nitrophenyl)amino)piperidine-1-carboxylic acid ⁇ /-butyl prepared in step 1 was dissolved in dichloromethane, trifluoroacetic acid was added thereto, and then at room temperature was stirred for 3 hours. After completion of the reaction, distilled water was added to the reaction solution, followed by extraction with dichloromethane. It was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain the title compound.
  • Step 4 Preparation of ⁇ (1-(adamantan-2-yl)piperidin-4-yl)-3-methoxybenzene-1,4-diamine 2021/111311 1 ⁇ (:1 ⁇ 2020/061350
  • step 2 of Example 1 ( ⁇ / ⁇ « ⁇ -((K-methoxy-gan-nitrophenyl)amino)adamantan- 1-ol instead of The title compound was synthesized in the same manner as in Example 1 using 1-(adamantan-2-yl)- ⁇ (3-methoxy-4-nitrophenyl)piperidin-4-amine.
  • Step 1 Preparation of ( «)-4-(4-((3-methoxy-4-nitrophenyl)amino)piperidin-1-yl)adamantan-1-ol
  • step 3 of Example 6 the title compound was synthesized in the same manner as in Example 6 using 5-hydroxyadamantan-2-one instead of adamantan-2-one.
  • Step 2 ( « )-4-(4-((4-amino-3-methoxyphenyl)amino)piperidine-1- 2021/111311 1 ⁇ (:1 ⁇ 2020/061350 days) Production of adamantane- 1-ol
  • step 2 of Example 1 ( ⁇ / ⁇ « ⁇ -((k-methoxy-gan-nitrophenyl)amino)adamantan-1-ol instead of ( ⁇ )-4-(4-((3)
  • the title compound was synthesized in the same manner as in Example 1 using -methoxy-4-nitrophenyl)amino)piperidin-1-yl)adamantan-1-ol.
  • Step 4 2-((2-((4-((1-(( ⁇ 5)-5-hydroxyadamantan-2-yl)piperidin-4-yl)amino)-2-methyl Preparation of oxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)_a 3-dimethylbenzamide 2021/111311 ?01/162020/061350
  • step 4 of Example 1 ( ⁇ 5) -4- ((4- ((4-chloro-5-
  • Step 1 (5)-4-(4-((3-methoxy-4-nitrophenyl)amino)piperidine-1_ 2021/111311 ?01/162020/061350 Sun) Production of Adamantane-1-ol
  • step 3 of Example 6 the title compound was synthesized in the same manner as in Example 6 using 5-hydroxyadamantan-2-one instead of adamantan-2-one.
  • Step 2 Preparation of (5)-4-(4-((4-amino-3-methoxyphenyl)amino)piperidin-1-yl)adamantan-1-ol
  • Step 2 of Example 1 ( ⁇ / ⁇ « ⁇ -((K-methoxy-gan-nitrophenyl)amino)adamantan-1-ol instead of ( )-4-(4-((3 -
  • the title compound was synthesized in the same manner as in Example 1 using methoxy-4-nitrophenyl)amino)piperidin-1-yl)adamantan-1-ol.
  • Step 3 (5)-4-(4-((4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)piperidin Diin- 1-yl) Preparation of adamantan- 1-ol
  • step 3 of Example 1 «--((liver-amino-3_ methoxyphenyl)amino)adamantan-1-ol instead of ( 5 )_4-(4-((4-amino-3-3-) 2021/111311 -01/162020/061350
  • the title compound was synthesized in the same manner as in Example 1 using methoxyphenyl)amino)piperidin-1-yl)adamantan-1-ol.
  • Step 1 4-((3-methoxy-4-nitrophenyl)oxy)piperidine-1-carboxylic acid butyl production
  • step 1 of Example 1 the title compound was prepared in the same manner as in Example 1, using 4-hydroxypiperidine-1-carboxylic acid ⁇ /-butyl instead of ⁇ 3 « 4-aminoadamantan-1-ol. synthesized.
  • Step 2 Preparation of 4-(3-methoxy-4-nitrophenoxy)piperidine
  • step 2 of Example 6 4-((3-methoxy-4-nitrophenyl)amino)piperidine-1-carboxylic acid ⁇ /-butyl instead of 4-((3-methoxy-4-nitro)
  • the title compound was synthesized in the same manner as in Example 6 using phenyl)oxy)piperidine-1-carboxylic acid ⁇ /-butyl.
  • Step 3 Preparation of 1-(adamantan-2-yl)- 4-(3-methoxy-4-nitrophenoxy)piperidine 2021/111311 ?01/162020/061350
  • the title compound was synthesized in the same manner.
  • Step 4 Preparation of 4-((1-(adamantan-2-yl)piperidin-4-yl)oxy)-2-methoxyaniline
  • step 2 of Example 1 ( ⁇ / ⁇ « ⁇ -((k-methoxy-gan-nitrophenyl)amino)adamantan-1-ol 1-(adamantan-2-yl)-
  • the title compound was synthesized in the same manner as in Example 1 using 4-(3-methoxy-4-nitrophenoxy)piperidine.
  • Step 5 ⁇ (4-((1-(adamantan-2-yl)piperidin-4-yl)oxy)-2-methoxyphenyl)-4-chloro-5-(trifluoromethyl )Preparation of pyrimidine-2-amine Methoxyphenyl )amino)adamantan-1-ol instead of 4-((1-(adamantan-2-yl)piperidin-4-yl)oxy)-2-methoxyaniline
  • the title compound was prepared in the same manner as in Example 1. 2021/111311 ?01/162020/061350 Synthesized.
  • Step 1 Preparation of 5-(3-methoxy-4-nitrophenoxy)adamantan-2-one In step 1 of Example 1, ⁇ 7? The title compound was synthesized in the same manner as in Example 1 using 5-hydroxyadamantan-2-one instead of 4-aminoadamantan-1-ol.
  • Step 1 2-((2-((2-methoxy-4-((4-morpholinoadamantan-1_yl)oxy)phenyl)amino)-5-(trifluoromethyl)pyrimidine- 4-yl) amino)- ⁇ 3_ dimethylbenzamide production 2-((2-((2-methoxy-4-((4-oxoadamantan-1_yl)oxy)phenyl)amino)-5-(trifluoromethyl)pyri prepared in Example 10 Midin-4-yl)amino)- ⁇ 3_ Dimethylbenzamide, morpholine, triacetoxysodium borohydride, tetrahydrofuran, and acetic acid were stirred at room temperature for 15 hours. Ice water was poured into the reaction solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain the title compound.
  • Step 1 2-((2-((4-((( )-4-((5)-3 -acetamidopyrrolidin-1-yl)adamantan-1-yl)oxy)-2 -Methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin_ 4-yl)amino)- ⁇ 3-dimethylbenzamide
  • the title compound was synthesized in the same manner as in Example 12, using (5)- ⁇ (pyrrolidin-3-yl)acetamide in step 1 of Example 12 instead of morpholine.
  • Step 1 2-((2-((4-(((5)-4-((5)-3-acetamidopyrrolidin-1-yl)adamantan-1-yl)oxy)- Preparation of 2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin_4-yl)amino)- ⁇ 3-dimethylbenzamide
  • the title compound was synthesized in the same manner as in Example 12 using (5)- ⁇ (pyrrolidin-3-yl)acetamide in step 1 of Example 12 instead of morpholine.
  • Step 1 Preparation of 4-(3-methoxy-4-nitrophenoxy)adamantane-1 -methyl carboxylate
  • step 1 of Example 1 the title compound was synthesized in the same manner as in Example 1, using methyl 4-hydroxyadamantane-1-carboxylate instead of ⁇ 3 « 4-aminoadamantan-1-ol.
  • Step 2 Preparation of 4-(4-amino-3-methoxyphenoxy)adamantane-1-carboxylate methyl
  • step 2 of Example 1 / ⁇ ⁇ -( -methoxy-between- 2021/111311 ?01/162020/061350
  • 4-(3-methoxy-4-nitrophenoxy)adamantane-1-carboxylate methyl instead of nitrophenyl)amino)adamantan-1-ol
  • the title compound was synthesized in the same manner as in Example 1.
  • Step 3 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)_3-methoxyphenoxy)adamantane- 1-methyl carboxylate
  • step 3 of Example 1 ( /"/ / ⁇ - ((trapped-amino- methoxyphenyl) amino) 4-(4-amino-3- methoxyphenoxy) instead of adamantan-1-ol
  • the title compound was synthesized in the same manner as in Example 1 using damantane_ 1-methyl carboxylate.
  • Step 1 2-((2-((2-methoxy-4-((5-(4-methylpiperazine-1-carbonyl)adamantan-2-yl)oxy)phenyl)amino)- Preparation of 5-(trifluoromethyl)pyrimidin-4-yl)amino)- ⁇ 3_ dimethylbenzamide 2021/111311 ?01/162020/061350
  • the title compound was synthesized in the same manner as in Example 18 using 1-methylpiperazine in Step 1 of Example 18 instead of methylamine hydrochloride.
  • Step 1 2-((2-((2-methoxy-4-((5-((5)-3-acetamidopyrrolidine-1-carbonyl)adamantan-2-yl)oxy )Phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-a 3-dimethylbenzamide 2021/111311 ?01/162020/061350
  • the title compound was synthesized in the same manner as in Example 18, using (5)- ⁇ (pyrrolidin-3-yl)acetamide in step 1 of Example 18 instead of methylamine hydrochloride. 0) 2 3 ): 5 8.37 (111, 111), 8.27 ( 111), 7.50 ( 3 ⁇ 4),
  • Step 1 Preparation of 4-((3-methoxy-4-nitrophenyl)amino)adamantane-1-methyl carboxylate 2021/111311 ?01/162020/061350
  • Step 1 of Example 1 the title compound was synthesized in the same manner as in Example 1, using methyl 4-aminoadamantane-1-carboxylate instead of ⁇ 3 « 4-aminoadamantan-1-ol.
  • Step 2 Preparation of 4-((4-amino-3-methoxyphenyl)amino)adamantane-1-carboxylate methyl
  • step 2 of Example 1 ( ⁇ / ⁇ « ⁇ -((k-methoxy-gan-nitrophenyl)amino)adamantan-1-ol instead of 4-((3-methoxy-4-nitride)
  • the title compound was synthesized in the same manner as in Example 1 using rhophenyl)amino)adamantane-1-carboxylate.
  • Step 3 4-((4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)adamantane-1-methyl carboxylate manufacture of Methoxyphenyl)amino)adamantan-1-ol instead of 4-((4-amino-3- 2021/111311 -01/162020/061350
  • the title compound was synthesized in the same manner as in Example 1 using methyl methoxyphenyl)amino)adamantane-1-carboxylate.
  • Step 4 4-((3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-2) Preparation of -yl)amino)phenyl)amino)adamantane- 1-methyl carboxylate In step 4 of Example 1, ( ⁇ )-4-((4-((4-chloro-5-)
  • Step 5 4-((3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-2) Preparation of -yl)amino)phenyl)amino)adamantane- 1-carboxylic acid
  • step 1 of Example 17 4-(3-methoxy-4-((4-((2-methyl-6-
  • Step 1 2-((2-((2-methoxy-4-((5-((5)-3-acetamidopyrrolidine-1-carbonyl)adamantan-2-yl)amino )Phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-a 3-dimethylbenzamide
  • the title compound was synthesized in the same manner as in Example 22 using (5)- ⁇ (pyrrolidin-3-yl)acetamide in step 6 of Example 22 instead of morpholine.
  • Step 2 Preparation of ⁇ (4-amino-3-methoxyphenyl)- 4-oxoadamantane- 1-carboxamide 2021/111311 ?01/162020/061350
  • step 2 of Example 1 ⁇ (3-methoxy-4-nitrophenyl) instead of (/"/ ⁇ / ⁇ - -(-methoxy-gan- nitrophenyl)amino)adamantan-1-ol )-
  • the title compound was synthesized in the same manner as in Example 1 using 4-oxoadamantane-1-carboxamide.
  • Step 3 ⁇ (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)_3-methoxyphenyl)-4 -oxoadamantane- 1-carboxa manufacture of mide
  • step 3 of Example 1 ⁇ (4-amino-3-methoxyphenyl)-4-oxoa instead of ( «--((liver-amino-3_ methoxyphenyl)amino)adamantan-1-ol
  • the title compound was synthesized in the same manner as in Example 1 using damantane-1-carboxamide.
  • Step 4 ⁇ (3-methoxy-4-((4-((2-methyl-6-(ethylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl) Amino) phenyl) -4 -oxoadamantane- 1- Carboxamide production 2021/111311 ?01/162020/061350
  • step 4 of Example 1 ( ⁇ )-4-((4-((4-chloro-5-
  • Step 5 ⁇ (3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl )Amino)phenyl)-4-morpholinoadamantane-1-carboxamide 2-((2-((2-methoxy-4-((4-oxoadamantan-1_yl)oxy)phenyl)amino)-5-(trifluoromethyl)p in step 1 of Example 12 rimidin-4-yl)amino)- ⁇ 3_ instead of dimethylbenzamide (3-methoxy-4-((4-((2-methyl-6-)
  • Step 1 ⁇ (3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl) Preparation of amino)phenyl)-4-(4-methylpiperazin-1-yl)adamantane-1-carboxamide
  • the title compound was synthesized in the same manner as in Example 25 using 4-methylpiperazine instead of morpholine in step 5 of Example 25.
  • Step 1 ( ⁇ )-4-((5)-3 -acetamidopyrrolidin- 1-yl)- ⁇ (3-methoxy-4- ((4-((2-methyl-6- ( Preparation of methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)adamantane-1-carboxamide
  • step 5 of Example 25 the title compound was prepared in the same manner as in Example 25, using (5)- ⁇ (pyrrolidin-3-yl)acetamide instead of morpholine. 2021/111311 ?01/162020/061350 Synthesized.
  • Step 1 ⁇ /-butyl ((35)-1-((7)-5-((3-methoxy- ⁇ (( ⁇ ((in methyl- ⁇ methylcarbamoylcenyl ⁇ amino) trifluoro) Preparation of romethyl-pyrimidin-ylamino-phenyl)carbamoyl)adamantan-2-yl)pyrrolidin-3-yl)carbamate 2021/111311 ?01/162020/061350 The title compound was synthesized in the same manner as in Example 25 using /-butyl(5)-pyrrolidin-3-ylcarbamate in step 5 of Example 25 instead of morpholine.
  • Step 1 ⁇ /-butyl ((35)-1-((7)-5-((3-methoxy- ⁇ (( ⁇ ((in methyl- ⁇ methylcarbamoylcenyl ⁇ amino) trifluoro) Preparation of romethyl-pyrimidin-ylamino-phenyl)carbamoyl)adamantan-2-yl)pyrrolidin-3-yl)carbamate
  • the title compound was synthesized in the same manner as in Example 25, using /-butyl (5)-pyrrolidin-3-ylcarbamate in step 5 of Example 25 instead of morpholine.
  • Step 2 ( )-4-((5)-3 -aminopyrrolidin-1-yl)- ⁇ (3-methoxy-4-((4-((2_methyl-6-(methylcarbamoyl) Preparation of )phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)adamantane-1-carboxamide 2021/111311 ?01/162020/061350 ⁇ /-butyl ((35)-1-(()-5-((3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl) prepared in step 1) )amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)carbamoyl)adamantan-2-yl)pyrrolidin-3-yl)carbamate with tetrahydrochloride dioxane It was dissolved in a phosphoric acid
  • Step 1 2-((2-((4-(1-((5)-5-hydroxyadamantan-2-yl)piperidin-4-yl)-2-methoxyphenyl)amino )- 5- (trifluoromethyl) pyrimidin-4-yl) amino) - ⁇ 3 - Preparation of dimethylbenzamide
  • step 4 of Example 1 ( ⁇ )-4-((4-((4-chloro-5-)
  • Step 1 2-((2-((4-(1-(( ⁇ 5)-5-hydroxyadamantan-2-yl)piperidin-4-yl)-2-methoxyphenyl) Amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-3-methylbenzamide
  • the title compound was prepared in the same manner as in Example 32 using 2-amino-3-methylbenzamide in Step 1 of Example 32 instead of 2-amino-water 3-dimethylbenzamide. 2021/111311 ?01/162020/061350 Synthesized.
  • Step 1 2-((2-((4-(1-((5)-5-hydroxyadamantan-2-yl)piperidin-4_yl)-2-methoxyphenyl)amino) -
  • Step 1 2-((2-((4-(1-((5)-5-hydroxyadamantan-2-yl)piperidin-4_yl)-2-methoxyphenyl)amino) -
  • Step 1 2-((2-((4-(1-((5)-5-hydroxyadamantan-2-yl)piperidin-4_yl)-2-methoxyphenyl)amino) -
  • 5-(trifluoromethyl)pyrimidin-4-yl)amino)-3-methylbenzamide 2021/111311 - 01/162020/061350 The title compound in the same manner as in Example 33, using 2-amino-3-methylbenzamide instead of 2-amino-water 3-dimethylbenzamide in Step 1 of Example 33 was synthesized.
  • Example 41 4-(4-(3-methoxy- ⁇ (( ⁇ ((yo-methyl to-methylcarbamoyl ⁇ phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl) )amino)phenyl)piperazin-1-yl)-methyladamantane-1-carboxyl samide
  • I 2.4 3 ⁇ 4 , within), 6.11 (111, lower), 3.82 (ex), 3.12 (111, tae), 2.80 (ex), 2.78 (ex), 2.70 (111, , 2.29 - 2.21 (111, ex) , 2.20 (eg), 2.14 - 2.07 (111, 23 ⁇ 4,
  • Example 42 4-(4-(3-methoxy- ⁇ ( ⁇ -((yo-methyl to-methylcarbamoyl ⁇ phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl Preparation of )amino)phenyl)piperazin-!-yl)adamantane-1 -carboxyl amide (Compound 42) 2021/111311 1 ⁇ (:1 ⁇ 2020/061350
  • Step 1 4-(4-(3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)_5-(trifluoromethyl)pyrimidine- Preparation of 2-yl)amino)phenyl)piperazin- 1-yl)- adamantane- 1 -carboxyl samide
  • the title compound was synthesized in the same manner as in Example 41 using dimethylamine hydrochloride instead of methylamine hydrochloride in step 1 of Example 41. 6 8.19 ( 111), 7.47 - 7.31 (111, year) , 6.55 ((1,
  • Step 3 2-((2-((4-(4-(5-aminoadamantan-2-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-(tri Preparation of fluoromethyl)pyrimidin-4-yl)amino)- ⁇ 3-dimethylbenzamide (9-fluoren-9-yl)methyl (4-(4-(3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino) prepared in step 2) )-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)adamantan-1-yl)carbamate was dissolved in acetonitrile and cooled to 106 .
  • Step 1 2-((2-((4-(4-(5-acrylamidoadamantan-2-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-( Preparation of trifluoromethyl)pyrimidin-4-yl)amino)- ⁇ 3-dimethylbenzamide 2-((2-((4-(4-(5-aminoadamantan-2-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5 prepared in Example 44 -(trifluoromethyl)pyrimidin-4-yl)amino)- ⁇ 3-dimethylbenzamide was dissolved in chloroform, potassium carbonate was added thereto, and the mixture was stirred. After slowly adding acryloyl chloride, the mixture was stirred at room temperature. The solvent was concentrated under reduced pressure and purified by column chromatography to obtain the title compound.
  • Example 3 In various human triple-negative breast cancer cell lines Measurement of compound 4, which is an adamantane derivative compound of the present invention inhibition of The activity was confirmed through the enzyme-linked immunosorbent assay [FAK ⁇ 397] as described above in various triple-negative breast cancer cell lines, and Table 3 below shows the values of 1 ⁇ 0 for each cell line.
  • the inhibitory activity ability of compound 4 of the present invention against various kinases is as follows. This kinase activity inhibition data is calculated from the results of kinase screening and profiling of Eurofins Company, and Table 4 below shows the inhibitory activity degree of the kinases inhibiting 70% or more among 107 screened kinases at a single concentration (lyM) of the compound ( % inhibition) and IC 5 o values for them.
  • adamantane derivatives according to the present invention are various triple-negative breast cancer cell lines 1 8-231, 1 8-453, 11070, _20, _549 and It was found that the activity was excellent.
  • Concentrations (0, 0.2, 0.5, 1, 2, 5, 10, 20 u M) of compound 4 were treated for 96 hours.
  • the cancer cell growth inhibitory effect of the compound was quantified using Cel Titer-Glo® 3D Cel Viabi lity Assay Kit (Pr omega, G9681) according to the manufacturer's instructions.
  • 1 shows the degree of inhibition of growth of cancer cell spheroids by treatment with different concentrations of compounds in MDA-MB-231 cells as a representative example of 3D spheroid assay.
  • Table 5 below shows the cancer cell spheroid growth inhibitory activity of Compound 4, an adamantane derivative compound of the present invention, in various triple-negative breast cancer cell lines including MDA-MB-231 as ICso values.
  • adamantane derivative according to the present invention had excellent cancer cell spheroid inhibitory activity at all concentrations.
  • adamantane derivatives according to the present invention are various triple-negative breast cancer cell lines 1 231, show- It was found that 16-453, 11070, _20, _549 and 3 ⁇ 45781 cancer cell spheroid growth inhibitory activity was excellent.
  • Example 5 Invasion analysis of 3D invasion inhibitory effect cells in the human triple-negative breast cancer cell line MDA-MB-231 was performed and quantified according to the 3D invasion assay. Briefly, MDA-MB-231 cells were cultured in a 96-well round plate (5xl0 3 /well) for 3 days to form cancer cell spheroids, and then fixed in a mixture of semi-solid Matrigel and type I collagen. A concentration of (1, 5 u M) of compound 4 was treated. The degree of infiltration was expressed as quantitative and graphed values based on the following formula (Equation 1), analyzed using a microscope (see Fig. 2) and imaging software, ImageJ, after 72 hours (see Fig. 3).
  • mice per group were included in the control group ( ⁇ 101), and the experimental groups with different concentrations of 3 groups (4-201 / 13 ⁇ 4, 4-401 /13 ⁇ 4 and 4-801 /13 ⁇ 4), and each compound was treated once daily.
  • the tumor volume of the mice was measured 3 times a week on every other day, and the mice were sacrificed on the 29th day after cell inoculation.
  • 4 is a graph showing the tumor volume calculated based on the following formula (Equation 2), with the starting date of drug treatment as 1 day.
  • Tumor volume (minus 3 ) [(Tumor minor diameter 2 X Tumor major diameter)/2]
  • Table 6 below shows the comparison of the average tumor growth of each compound treatment group compared to the average tumor growth of the control group in the following formula (Formula 3) based on calculated and shown.
  • %TGI 100 X [1- (TV f inal treated- TV i nit ial treated )/ (TV f inal control- TV i nitial control ) 1

Abstract

The present invention provides novel adamantane derivatives as inhibitors of a focal adhesion kinase, pharmaceutically acceptable salts thereof, stereoisomer thereof, a hydrate or solvate thereof, and a pharmaceutical composition comprising same.

Description

2021/111311 ?01/162020/061350 2021/111311 ?01/162020/061350
【명세서】 【Specification】
【발명의 명칭】 국소 부착 키나아제 저해제로서 신규한 아다만탄 유도체 [Title of the Invention] Novel adamantane derivative as a topical adhesion kinase inhibitor
【기술분야】 본 발명은 국소 부착 키나아제 저해제로서 신규한 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물 및 이를 포함하는 약학적 조성물에 관한 것이다 . [Technical Field] The present invention relates to a novel adamantane derivative as a local adhesion kinase inhibitor, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or solvate thereof, and a pharmaceutical composition comprising the same.
【배경기술】 암은 세계적으로 사망률이 높은 질병으로 그 발생 빈도가 점점 늘어가고 있음에도 불구하고 아직까지도 현대 의학에서 적절한 치료 방법을 개발하지 못한 가장 두려운 난치병으로 알려져 있다 . 현재 개발된 항암제는 주로 세포 성장 기전을 억제하거나 세포 사멸을 유도하는 기전과 관련된 약물로서 암세포뿐만 아니라 정상세포에도 그 영향을 미쳐 세포 독성을 나타내는 등의 부작용이 있다 . 최근 의생물학 및 분자생물학적 기술이 발달됨에 따라 암세포만의 고유한 특성들이 밝혀지고， 게놈 염기서 열 분석을 통하여 이 러한 특성에 관여하는 새로운 분자 수준의 표적 이 많이 발굴되었으며 이를 표적으로 하는 표적항암제들의 개발이 활발히 이루어지고 있다 . 일반적으로 세포 내에 존재하는 신호전달체계는 서로 유기적으로 연결되어 복잡한 메커니즘을 형성함으로써 세포의 증식， 성장， 전이， 사멸 등을 조절한다 . 신호전달체계에서 단백질 티로신 키나제는 세포 내의 조절기능에 중요한 역할을 담당한다. 많은 질환들이 단백질 티로신 키나제에 의해 촉발되는 비정상적 세포 반응과 관련이 있다. 이들 질환에는 자가면역 질환， 염증성 질환， 골 질환， 대사성 질환， 신경학 및 신경변성 질환， 암， 심혈관 질환， 알레르기 및 천식， 알츠하이머병， 바이러스 질환 및 호르몬 관련 질환이 있으며， 특히 암세포에서는 단백질 티로신 키나제의 비정상적인 발현 및 변이가 많이 관찰되기 때문에 의약 화학에서는 항암 치료제로서 효과적인 단백질 티로신 키나제 억제제를 개발하기 위해서 많은 연구가 이루어지고 있는 실정이다. 국소 부착 키나제 (focal adhesion kinase, FAK)는 PTK2 유전자에 의해 코딩되는 단백질로 세포질 내에 존재하는 비수용체 티로신 키나제로서 인테그린 및 성장인자 수용체로부터 신호를 전달받아 세포의 성장， 증식， 부착， 이동， 침윤 및 암 줄기세포의 자가 재생산의 조절에 중요한 역할을 하는 것으로 알려져 있다. FAK은 Y397의 자가인산화를 통하여 조절되고 활성화되며， 다른 티로신 키나제인 Src 단백질의 SH2 도메인을 통하여 자기인산화된 Y397 에 결합하고， Src 단백질은 FAK 의 Y925 를 인산화하여， 어답터 단백질인 Grb2 를 유인하고， 세포 증식을 조절하는데 관여하는 ras 및 MAP 키나제 경로의 활성화를 유도한다. 정상적인 세포의 경우 FAK을 경유한 신호 전달은 매우 엄격하게 조절되지만， 종양으로 변한 세포에서는 FAK이 과발현되고 활성화되어 악성 종양의 여러 가지 특징을 야기한다. FAK의 과발현은 종양 세포의 증식， 침윤 및 전이를 촉진시키고 암세포 사멸을 억제하며 혈관 신생을 증가시킴으로써 종양화 과정 (종양형성， 침윤， 전이 등)에 중추적인 역할을 하는 것으로 알려져 있다. 이러한 과정에의 FAK 연관성을 확인한 연구 결과， FAK 안티센스 올리고뉴클레오티드로 FAK 활성을 억제한 종양 세포에서는 정상적인 세포 부착이 억제되어 세포사멸화 과정 (apoptosis, 아폽토시스)을 겪는 것을 관찰하였으며， FAK 발현이 결핍된 섬유모세포에서는 정상 세포와 비교하여 세포 모양이 방추형에서 원형 모양으로 변형되었고， 화학주성 신호에 대한 세포 이동을 억제한다고 보고하였으며， 이러한 현상들은 FAK 의 재발현에 의하여 다시 원상태로 복귀함을 확인하였다. [Background Art] Cancer is known as the most feared incurable disease for which modern medicine has not yet developed an appropriate treatment method despite the increasing incidence of cancer as a disease with high mortality worldwide. Currently developed anticancer drugs mainly inhibit the cell growth mechanism or are related to the mechanism of inducing apoptosis, and have side effects such as cytotoxicity by affecting not only cancer cells but also normal cells. With the recent development of medical biology and molecular biology technology, unique characteristics of cancer cells have been revealed, and many new molecular-level targets involved in these characteristics have been discovered through genome sequencing. Development is actively taking place. In general, signal transduction systems existing in cells are organically linked to each other to form complex mechanisms, thereby controlling cell proliferation, growth, metastasis, and death. In the signaling pathway, protein tyrosine kinases play an important role in cellular regulatory functions. Many diseases are associated with abnormal cellular responses triggered by protein tyrosine kinases. These diseases include autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, viral diseases and hormone-related diseases. Since a lot of abnormal expression and mutation are observed, many studies are being made in pharmaceutical chemistry to develop an effective protein tyrosine kinase inhibitor as an anticancer treatment. Focal adhesion kinase (FAK) is a protein encoded by the PTK2 gene, which is a non-receptor tyrosine kinase present in the cytoplasm and receives signals from integrin and growth factor receptors for cell growth, proliferation, adhesion, migration, invasion and It is known to play an important role in the regulation of self-reproduction of cancer stem cells. FAK is regulated and activated through autophosphorylation of Y397, and binds to self-phosphorylated Y397 through the SH2 domain of Src protein, which is another tyrosine kinase, and Src protein phosphorylates Y925 of FAK, attracting adapter protein Grb2, It induces activation of the ras and MAP kinase pathways involved in regulating cell proliferation. In the case of normal cells, signal transduction via FAK is very tightly regulated, but in cells transformed into tumors, FAK is overexpressed and activated, causing various characteristics of malignant tumors. It is known that overexpression of FAK plays a pivotal role in the oncogenic process (tumor formation, invasion, metastasis, etc.) by promoting proliferation, invasion and metastasis of tumor cells, inhibiting cancer cell death, and increasing angiogenesis. FAK in these processes As a result of the study confirming the correlation, it was observed that normal cell adhesion was inhibited in tumor cells in which FAK activity was inhibited with FAK antisense oligonucleotides and undergoes apoptosis (apoptosis, apoptosis). In fibroblasts deficient in FAK expression, normal cells It was reported that the cell shape was changed from a spindle-shaped to a circular shape as compared with chemotactic signals and suppressed cell migration in response to chemotactic signals, and it was confirmed that these phenomena returned to their original state by re-expression of FAK.
FAK 단백질 및 mRNA는 유방암， 대장암， 폐암， 난소암， 전립선암 등 다양한 고형암뿐만 아니라 급성 골수성 백혈병과 같은 혈액암에서 과발현되는 것으로 확인되었으며， 활성을 나타내는 인산화된 FAK 가 정상 조직보다 악성 조직에서 증가되어 있고， 특히 암 환자에서 FAK의 활성이 높을수록 예후가 좋지 않은 것으로 보아 FAK의 활성이 인체 암의 진행이나 전이 과정에 중요하게 관여하는 것으로 판단된다. 또한 FAK 의 유일한 아형인 prol ine-rich tyrosine kinase 2 (PYK2)는 신경세포에 가장 많이 분포하는데， 최근에 소세포폐암， 전립선암， 간세포암， 신경교종 등의 항암제 개발의 분자표적으로서 가치가 확인되고 있는 중이다. 이처럼 FAK의 활성 저해를 통한 항암 효과가 기대되면서 FAK의 활성을 저해하는 저분자 화합물들이 세계적으로 20 여종 개발되고 있으며， 이 중에서 TAE226은 Taxane-sensitive cel l 1 ine(HeyA8, SK0V3ip)과 Taxane-resistant cel l l ine(HeyA8-MDR)으로 형성된 세 종류의 유방암 동물모델에서 단독 또는 도세탁셀 ((100아3 )의 병용투여에 의해 종양의 크기가 87 - 90% 감소하는 탁월한 효능을 보였지만， 인슐린 수용체 (insul in receptor)를 억제하여 예기치 않은 글루코스 대사작용 억제 및 혈중농도 저하 등의 심각한 부작용 때문에 전임상 연구 단계에서 중단되었고， 현재에는 PF-04554878과 GSK2256098이 임상 단계 연구가 진행 중에 있다. FAK protein and mRNA were found to be overexpressed in various solid cancers such as breast cancer, colorectal cancer, lung cancer, ovarian cancer, prostate cancer, as well as blood cancers such as acute myeloid leukemia, and phosphorylated FAK showing activity increased in malignant tissues than in normal tissues In particular, the higher the activity of FAK in cancer patients, the poorer the prognosis, so it is judged that the activity of FAK is important in the progression or metastasis of human cancer. In addition, proline-rich tyrosine kinase 2 (PYK2), the only subtype of FAK, is most widely distributed in neurons, and has recently been valued as a molecular target for the development of anticancer drugs such as small cell lung cancer, prostate cancer, hepatocellular cancer, and glioma. there is As such, anti-cancer effects through inhibition of FAK activity are expected, and 20 types of low-molecular compounds that inhibit FAK activity are being developed worldwide. Among them, TAE226 is Taxane-sensitive cell 1 ine (HeyA8, SK0V3ip) and Taxane-resistant cell. In three types of breast cancer animal models formed with lline (HeyA8-MDR), either alone or in combination with docetaxel ((100A3) showed excellent efficacy in reducing the size of the tumor by 87 - 90%, but insulin receptor (insul in receptor), resulting in unexpected Due to serious side effects such as inhibition of glucose metabolism and lowering of blood concentration, the preclinical research stage was stopped, and PF-04554878 and GSK2256098 are currently in clinical stage research.
［선행기술문헌］ [Prior art literature]
（비특허문헌 1） Cancer Res.2007， 67： 10976-10983 (Non-Patent Document 1) Cancer Res. 2007, 67: 10976-10983
（비특허문헌 2） Expert Opin. Investing.Drugs,2010, 19:777-788 (Non-Patent Document 2) Expert Opin. Investing. Drugs, 2010, 19:777-788
【발명의 상세한 설명】 【Detailed Description of the Invention】
【기술적 과제】 본 발명의 일 목적은 상기와 같은 문제점을 해결하기 위한 것으로 국소 부착 키나아제 저해제로서 신규한 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물을 제공하는 것이다. 본 발명의 또 다른 목적은 상기 국소 부착 키나아제 저해제로서 신규한 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물을 유효성분으로 포함하는 약학적 조성물을 제공하는 것이다. 본 발명의 또 다른 목적은 상기 국소 부착 키나아제 저해제로서 신규한 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물을 유효성분으로 포함하는， FAK관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다. 본 발명의 또 다른 목적은 상기 국소 부착 키나아제 저해제로서 신규한 2021/111311 ?01/162020/061350 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물의 치료학적으로 유효한 양을 개체에 투여하는 단계를 포함하는， 관련 질환의 예방 또는 치료 방법을 제공하는 것이다. 본 발명의 또 다른 목적은
Figure imgf000006_0001
관련 질환의 예방 또는 치료를 위한 상기 국소 부착 키나아제 저해제로서 신규한 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 이성질체， 이의 수화물 또는 용매화물의 용도를 제공하는 것이다. 본 발명의 또 다른 목적은
Figure imgf000006_0002
관련 질환의 예방 또는 치료용 약제의 제조를 위한 상기 국소 부착 키나아제 저해제로서 신규한 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 이성질체， 이의 수화물 또는 용매화물의 용도를 제공하는 것이다. [Technical Problem] An object of the present invention is to solve the above problems, and as a local adhesion kinase inhibitor, a novel adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof is provided. will do Another object of the present invention is to provide a pharmaceutical composition comprising a novel adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof as an active ingredient as the local adhesion kinase inhibitor. . Another object of the present invention is a novel adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer, a hydrate or a solvate thereof, as an active ingredient as the local adhesion kinase inhibitor. Prevention of FAK-related diseases or To provide a pharmaceutical composition for treatment. Another object of the present invention is to provide a novel topical adhesion kinase inhibitor. 2021/111311 - 01/162020/061350 of adamantane derivative, its pharmaceutically acceptable salt, its stereoisomer, its hydrate or solvate comprising administering to an individual a therapeutically effective amount of a related disease To provide a method of prevention or treatment. Another object of the present invention is
Figure imgf000006_0001
To provide the use of a novel adamantane derivative, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate or a solvate thereof as the local adhesion kinase inhibitor for the prevention or treatment of related diseases. Another object of the present invention is
Figure imgf000006_0002
To provide the use of a novel adamantane derivative, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate or a solvate thereof as the local adhesion kinase inhibitor for the preparation of a medicament for the prevention or treatment of related diseases.
【기술적 해결방법】 본 발명의 국소 부착 키나아제 저해제로서 신규한 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물은 하기 화학식 1로 나타낸다. [Technical Solution] A novel adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof as a local adhesion kinase inhibitor of the present invention is represented by the following formula (1).
[화학식 1] [Formula 1]
2021/111311 ?01/162020/061350
Figure imgf000007_0001
상기 화학식 1에서， 및 는 각각 독립적으로 단결합， -1()알킬렌， ¾-1()알케닐렌， 02- 10알키닐렌， (1¾) -， - =0)- 1¾) -， (1¾)-〔:(=0) -， -0(=0)-, -0 -, -0(=0)-0 -, - 1¾0-〔:(=0)-0 -， (1¾)-3(=0) -, (1¾)-3(=0)2 -, - =0)(= -1¾) -, 또는 - 이고; 2021/111311 ?01/162020/061350
Figure imgf000007_0001
In Formula 1, and are each independently a single bond, - 1 () alkylene, ¾ - 1 () alkenylene, 0 2 - 10 alkynylene, (1¾) -, - = 0) - 1¾) -, ( 1¾)-[:(=0) -, -0(=0)-, -0 -, -0(=0)-0 -, - 1¾0-[:(=0)-0 -, (1¾)- 3(=0) -, (1¾)-3(=0) 2 -, - =0)(= -1¾) -, or -;
¾ 및 ¾는 각각독립적으로 -1()헤테로사이클로알킬렌， ¾-1()사이클로알킬렌， ¾-16아릴렌 또는 04,헤테로아릴렌이고; ¾ and ¾ are each independently -1 () heterocycloalkylene, ¾- 1 () cycloalkylene, ¾- 16 arylene or 0 4 , heteroarylene;
¾는 II， -1()알킬， ¾-1()알케닐， -0^3, =0, - -1¾， -· ᄄ=0)-1¾ 또는 01- 10헤테로사이클로알킬이고， 묘4는 -0-1¾이고; ¾ is II, - 1 () alkyl, ¾- 1 () alkenyl, -0 ^ 3, = 0, - -1¾, - · tt = 0) -1¾ 0 or 1-10, and heterocycloalkyl, cat 4 is -0-1¾;
¾ 및 ¾은 각각 독립적으로 II또는 -10알킬이고; 묘7는 _0?3 또는 할로겐 원자이고;
Figure imgf000007_0002
킬이고; 此 II， I) 및 (1는 각각 독립적으로 0 또는 1이다. 일 실시예에서， 상기 화학식 1의 ¾ 및 ¾는 각각 독립적으로， 2021/111311 ?01/162020/061350
Figure imgf000008_0001
독립적으로
Figure imgf000008_0004
Figure imgf000008_0002
Figure imgf000008_0005
¾ and ¾ are each independently II or -10 alkyl; Myo 7 is _ 0? 3 or a halogen atom;
Figure imgf000007_0002
kill;此 II, I) and (1 are each independently 0 or 1. In one embodiment, ¾ and ¾ of Formula 1 are each independently, 2021/111311 ?01/162020/061350
Figure imgf000008_0001
independently
Figure imgf000008_0004
Figure imgf000008_0002
Figure imgf000008_0005
0 V
Figure imgf000008_0006
이고 ;
Figure imgf000008_0003
2021/111311 1^(:1^2020/061350 일 실시예에서， 상기 화학식 1로 나타내는 화합물은 하기 화학식 2로 나타내는 화합물일 수 있다. 0 V
Figure imgf000008_0006
ego ;
Figure imgf000008_0003
2021/111311 1^(:1^2020/061350 In one embodiment, the compound represented by Formula 1 may be a compound represented by Formula 2 below.
［화학식 2］
Figure imgf000009_0002
몰포리딘일이고; [Formula 2]
Figure imgf000009_0002
is morpholidinyl;
¾는 II또는 -10알킬이고;
Figure imgf000009_0001
킬이고; II， I) 및 (1는 각각 독립적으로 0 또는 1이다. ¾ is II or -10 alkyl;
Figure imgf000009_0001
kill; II, I) and (1 are each independently 0 or 1.
【발명의 효과】 본 발명의 국소 부착 키나아제 저해제로서 신규한 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물은 FAK와 Pyk2(FAK2)의 활성을 선택적으로 저해하면서 동시에 인슐린 수용체 (insul in receptor , Ins-R) 활성은 저해하지 않는 작용 효과를 나타낸다 . 본 발명에 따른 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물은 FAK의 비정상적인 활성을 억제함으로써， FAK의 비정상적인 활성을 억제에 의해 유도되는 비정상 세포 성장 질환을 예방 및 치료에 유용하게 이용할 수 있다. [Effect of the Invention] As a local adhesion kinase inhibitor of the present invention, the novel adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer, a hydrate or a solvate thereof, selectively inhibits the activity of FAK and Pyk2 (FAK2) At the same time, it exhibits an action effect that does not inhibit insulin receptor (Ins-R) activity. The adamantane derivative, its pharmaceutically acceptable salt, its stereoisomer, its hydrate or solvate according to the present invention inhibits the abnormal activity of FAK, thereby inhibiting the abnormal activity of FAK Abnormal cell growth disease induced by inhibition It can be usefully used for prevention and treatment.
【도면의 간단한 설명】 도 1은 본 발명의 아다만탄 유도체 화합물의 암 세포 구상체의 성장 저해 정도를 분석하기 위한 3D spheroid assay 결과를 나타낸 것이다. 도 2는 본 발명의 아다만탄 유도체 화합물의 인간 삼중음성유방암 세포주인 MDA-MB-231의 3D 침윤 저해 정도를 분석하기 위한 현미경 분석 결과이다. 도 3은 본 발명의 아다만탄 유도체 화합물의 인간 삼중음성유방암 세포주인 MDA-MB-231의 3D 침윤 저해 정도를 분석한 결과이다. 도 4는 본 발명의 아다만탄 유도체화합물의 삼중음성유방암 이종이식 마우스 모델 (xenograft mouse model)에서의 종양 성장 저해 정도를 분석한 결과이다. 2021/111311 ?01/162020/061350 [Brief Description of the Drawings] FIG. 1 shows the results of a 3D spheroid assay for analyzing the growth inhibition of cancer cell spheroids of the adamantane derivative compound of the present invention. 2 is a microscopic analysis result for analyzing the 3D invasion inhibition degree of the human triple-negative breast cancer cell line MDA-MB-231 of the adamantane derivative compound of the present invention. 3 is a result of analyzing the 3D invasion inhibition degree of the adamantane derivative compound of the present invention, MDA-MB-231, a human triple-negative breast cancer cell line. 4 is a result of analyzing the degree of tumor growth inhibition of the adamantane derivative compound of the present invention in a triple-negative breast cancer xenograft mouse model. 2021/111311 ?01/162020/061350
【발명을 실시하기 위한 구체적인 내용】 이하， 본 출원에서 사용한 용어는 단지 특정한 실시예를 설명하기 위해 사용된 것으로서 본 발명을 한정하려는 의도가 아니다. 단수의 표현은 문맥상 명백하게 다르게 뜻하지 않는 한， 복수의 표현을 포함한다. 본 출원에서， ”포함하다" 또는 "가지다” 등의 용어는 명세서 상에 기재된 특징， 단계， 동작， 구성요소， 부분품 또는 이들을 조합한 것이 존재함을 지정하려는 것이지， 하나 또는 그 이상의 다른 특징들이나 단계， 동작， 구성요소， 부분품 또는 이들을 조합한 것들의 존재 또는 부가 가능성을 미리 배제하지 않는 것으로 이해되어야 한다. 다르게 정의되지 않는 한， 기술적이거나 과학적인 용어를 포함해서 여기서 사용되는 모든 용어들은 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에 의해 일반적으로 이해되는 것과 동일한 의미를 가지고 있다. 일반적으로 사용되는 사전에 정의되어 있는 것과 같은 용어들은 관련 기술의 문맥 상 가지는 의미와 일치하는 의미를 가지는 것으로 해석되어야 하며， 본 출원에서 명백하게 정의하지 않는 한， 이상적이거나 과도하게 형식적인 의미로 해석되지 않는다. 아다만탄 유도체 , 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체 , 이의 수화물 또는 용매화물 본 발명에서， 작용기의 XX” 의 표시에서 는 탄소（0의 개수를 나타내고， 0x1는 탄소수가 X 이상 이하를 갖는 작용기를 의미하는 것으로 한다. 본 발명에서， 용어 ”치환된"은 주쇄의 하나 이상의 탄소상의 수소를 대체하는 치환기를 갖는 부분을 나타낸다. ”치환” 또는 "〜로 치환된"은 이러한 치환이 치환된 원자 및 치환체의 허용되는 가에 따르며， 치환에 의해 안정한 화합물 예를 들어， 재배열， 고리화， 제거 등에 의해 자연적으로 변형되지 않는 화합물을 유도한다는 암묵적 조건을 포함하는 것으로 정의한다. 본 발명에서， “단결합” 은 Li 또는 L2에 인접하는 원자 또는 원자단끼리 직접 결합하고 있는 경우를 의미한다. 본 발명에서， “알킬” 은 선형（또는 직쇄형， l inear） 포화탄화수소기 또는 분지형（또는 측쇄형， branched） 포화탄화수소기를 의미하는 것으로， 메틸， 에틸， n_ 프로필， 이소프로필， n-부틸， sec-부틸， 이소부틸， tert-부틸， n_펜틸， n_핵실， n_ 헵틸 등을 포함하며， 여기에 한정되는 것은 아니다. 본 발명에서， “알킬렌” 은 상기와 같이 정의된 알킬로부터 유도된 2가의 작용기를 의미하는 것이다. 본 발명에서， “알케닐” 은 탄소 사이의 적어도 1개의 이중결합을 포함하는 불포화탄화수소기를 의미하는 것이고， “알키닐” 은 탄소 사이의 적어도 1개의 삼중결합을 포함하는 불포화탄화수소기를 의미하는 것이다. 본 발명에서， “알케닐렌” 은 상기와 같이 정의된 알케닐로부터 유도된 2가의 작용기를 의미하는 것이고， “알키닐렌” 는 상기와 같이 정의된 알키닐로부터 유도된 2가의 작용기를 의미하는 것이다. 본 발명에서， “할로겐 원자” 는 F, Cl , Br 또는 I를 의미하는 것이다. 본 발명에서， “아릴” 은 일환 방향족 또는 다환 방향족과， 일환 또는 다환 방향족에 포화탄화수소 고리가 융합된 구조도 포함한다. 아릴은 페닐기， 바이페닐， 2021/111311 ?01/162020/061350 나프탈렌일， 테트라하이드로나프탈렌일， 안트라센일， 페난트렌일， 피렌일 등을 포함하며， 여기에 한정되는 것은 아니다. 본 발명에서， “헤테로아릴” 은 상기 아릴기에서 적어도 1개 이상의 탄소원자가 질소 )， 산소 (0) 또는 황比)으로 치환된 일환 또는 다환의 헤테로 고리를 의미하는 것이다. 헤테로아릴은 피리디닐， 티오페닐， 트리아졸릴， 테트라졸릴， 벤조디옥솔일， 벤조티아졸일， 벤조티오펜일， 퀴놀린일， 인돌릴， 이소인돌릴， 벤조퓨란일， 벤조피롤일， 퓨란일， 피롤릴， 티아졸릴， 이소티아졸릴， 이미다졸릴， 피라졸릴， 옥사졸일， 이소옥사졸일， 피라진일， 피리다진일， 피리미딘일， 이소퀴놀린일， 카바졸릴， 벤조옥사졸일， 벤조다이옥사졸일， 벤조다이옥신일， 벤조이미다졸릴， 디하이드로벤조티오펜일， 디하이드로벤조퓨란일， 퓨린일， 인돌리진일， 크로만일， 크로멘일， 디하이드로벤조디옥신일 등을 포함하며， 여기에 한정되는 것은 아니다. 본 발명에서， “사이클로알킬” 은 고리를 포함하는 명시된 수의 탄소원자를 일반적으로 갖는 포화탄화수소 고리를 의미하며 포화탄화수소 고리는 일환 및 다환，[Specific content for carrying out the invention] Hereinafter, the terms used in the present application are used only to describe specific embodiments and are not intended to limit the present invention. The singular expression includes the plural expression unless the context clearly dictates otherwise. In the present application, terms such as “comprise” or “have” are intended to designate that a feature, step, operation, component, part, or combination thereof described in the specification exists, and one or more other features or steps , it should be understood that the existence or addition of operations, components, parts or combinations thereof is not excluded in advance. Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. Terms such as those defined in commonly used dictionaries should be interpreted as having meanings consistent with the meanings in the context of the related art, and unless explicitly defined in the present application, they should not be interpreted in an ideal or excessively formal meaning. does not Adamantane derivatives, pharmaceutically acceptable salts thereof, stereoisomers thereof, hydrates or solvates thereof It shall mean a functional group which has. In the present invention, the term “substituted” refers to hydrogen on one or more carbons of the main chain. Represents a moiety having a substituent to be substituted. "Substitution" or "substituted with" depends on the permissible value of the atom and substituent in which the substitution is substituted, and a compound that is stable by substitution, for example, a compound that is not naturally modified by rearrangement, cyclization, removal, etc. It is defined as including an implicit condition that induces In the present invention, “single bond” refers to a case in which atoms or groups of atoms adjacent to Li or L2 are directly bonded to each other. In the present invention, "alkyl" refers to a linear (or straight chain, l inear) saturated hydrocarbon group or a branched (or branched, branched) saturated hydrocarbon group, methyl, ethyl, n_ propyl, isopropyl, n-butyl , including, but not limited to, sec-butyl, isobutyl, tert-butyl, n_pentyl, n_nuclear, n_heptyl, and the like. In the present invention, “alkylene” refers to a divalent functional group derived from alkyl as defined above. In the present invention, “alkenyl” refers to an unsaturated hydrocarbon group containing at least one double bond between carbons, and “alkynyl” refers to an unsaturated hydrocarbon group containing at least one triple bond between carbons. In the present invention, “alkenylene” refers to a divalent functional group derived from alkenyl as defined above, and “alkynylene” refers to a divalent functional group derived from alkynyl as defined above. In the present invention, "halogen atom" means F, Cl , Br or I. In the present invention, "aryl" also includes a monocyclic aromatic or polycyclic aromatic and a monocyclic or polycyclic aromatic structure in which a saturated hydrocarbon ring is fused. Aryl is a phenyl group, biphenyl, 2021/111311 ?01/162020/061350 Naphthalenyl, tetrahydronaphthalenyl, anthracenyl, phenanthrenyl, pyrenyl, etc., but are not limited thereto. In the present invention, “heteroaryl” refers to a monocyclic or polycyclic heterocyclic ring in which at least one carbon atom in the aryl group is substituted with nitrogen), oxygen (0), or sulfur). Heteroaryl is pyridinyl, thiophenyl, triazolyl, tetrazolyl, benzodioxolyl, benzothiazolyl, benzothiophenyl, quinolinyl, indolyl, isoindolyl, benzofuranyl, benzopyrrolyl, furanyl, p Rollyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, carbazolyl, benzoxazolyl, benzodioxazolyl, including benzodioxinyl, benzoimidazolyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, purinyl, indolizinyl, chromanyl, chromenyl, dihydrobenzodioxinyl, etc., but limited thereto it is not In the present invention, "cycloalkyl" means a saturated hydrocarbon ring generally having the specified number of carbon atoms including the ring, and the saturated hydrocarbon ring is monocyclic and polycyclic;
2개 이상의 고리가 한쌍 이상의 탄소원자를 공유하고 있는 고리 구조를 모두 포함하는 의미이다. 사이클로알킬은 사이클로핵실， 사이클로헵틸， 사이클로옥틸， 테트라하이드로나프탈렌일， 아다만틸 등을 포함하며， 여기에 한정되는 것은 아니다. 본 발명에서， “헤테로사이클로알킬” 은 질소 )， 산소 (0) 및 황比)으로부터 독립적으로 선택된 1 내지 4개의 헤테로원자를 함유하는 포화된 일환 및 다환의 헤테로 고리 또는 2개 이상의 고리가 한쌍 이상의 탄소원자를 공유하고 있는 고리 구조를 의미한다. 헤테로사이클로알킬은 옥시란일， 옥세탄일， 모포린닐， 2021/111311 ?01/162020/061350 티에탄일， 피롤리딘일， 피페리딘일 ， 피페라진일， 테트라하이드로퓨란일， 테트라하이드로티오펜일， 테트라하이드로피란일， 테트라하이드로티오피란일， 6 - 아자바이사이클로［3.2.1］옥탄일 등을 포함하며， 여기에 한정되는 것은 아니다. 본 발명에서의 “사이클로알킬렌” 은 사이클로알킬로부터 유도된 2가의 작용기를 의미하는 것이고， “헤테로사이클로알킬렌” 은 헤테로사이클로알킬로부터 유도된 2가의 작용기를 의미하는 것이다. 본 발명에 따른 화학식 1로 나타내는 아다만탄 유도체는 하기 표에 나타낸 화합물들로 이루어진 군으로부터 선택된 어느 하나의 화합물일 수 있다.
Figure imgf000014_0001
2021/111311 1^(:1^2020/061350
Figure imgf000015_0001
Figure imgf000016_0001
It is meant to include all ring structures in which two or more rings share one or more pairs of carbon atoms. Cycloalkyl includes, but is not limited to, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydronaphthalenyl, adamantyl, and the like. In the present invention, "heterocycloalkyl" is a saturated monocyclic and polycyclic hetero ring containing 1 to 4 heteroatoms independently selected from nitrogen), oxygen (0) and sulfur), or two or more rings are at least one pair It refers to a ring structure in which carbon atoms are shared. Heterocycloalkyl is oxiranyl, oxetanyl, morpholinyl, 2021/111311 ?01/162020/061350 Thietanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, 6 - azaby cyclo[3.2.1]octanyl, and the like, but are not limited thereto. In the present invention, “cycloalkylene” refers to a divalent functional group derived from cycloalkyl, and “heterocycloalkylene” refers to a divalent functional group derived from heterocycloalkyl. The adamantane derivative represented by Formula 1 according to the present invention may be any one compound selected from the group consisting of compounds shown in the following table.
Figure imgf000014_0001
2021/111311 1^(:1^2020/061350
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
2021/111311 1^(:1^2020/061350
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000021_0002
Figure imgf000019_0001
2021/111311 1^(:1^2020/061350
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000021_0002
Figure imgf000022_0001
Figure imgf000023_0001
본 발명에서， “입체 이성질체” 는 부분입체 이성질체（diastereomer） 및 광학 이성질체（opt ical isomer）를 포함하는 것으로， 광학이성질체는 거울상 이성질체（enant iomer）뿐만 아니라 거울상 이성질체의 혼합물 및 라세미체까지 모두 포함한다 2021/111311 ?01/162020/061350 본 발명에서， “약학적으로 허용가능한 염 ” 은 의약업계에서 통상적으로 사용되는 염을 의미하며， 예를 들어 칼슘， 포타슘， 소듐 및 마그네슘 등으로 제조된 무기이온염， 염산， 질산， 인산， 브롬산， 요오드산， 과염소산， 하이드로 아이오딕산 및 황산 등으로 제조된 무기산염 ; 아세트산， 트라이플루오로아세트산， 시트르산， 말레인산， 숙신산， 옥살산， 벤조산， 타르타르산， 푸마르산， 만데르산， 프로피온산， 젖산， 글리콜산， 글루콘산， 갈락투론산， 글루탐산， 글루타르산， 글루쿠론산， 아스파르트산， 아스코르브산， 카본산 및 바닐릭산 등으로 제조된 유기산염 ; 메탄설폰산， 에탄설폰산， 벤젠설폰산， ］3 -톨루엔설폰산 및 나프탈렌설폰산 등으로 제조된 설폰산염 ; 글리신， 아르기닌 및 라이신 등으로 제조된 아미노산염 ; 및 트라이메틸아민， 트라이에틸아민， 암모니아， 피리딘 및 피콜린 등으로 제조된 아민염 등이 있으나， 열거된 이들 염에 의해 본 발명에서 의미하는 염의 종류가 한정되는 것은 아니다. 본 발명의 ‘수화물’ 은 아다만탄 유도체， 이의 이성질체 또는 이의 약학적으로 허용가능한 염과 물이 비공유적 분자간 힘으로 결합되어 있는 것으로 화학양론적 또는 비화학양론적의 양의 물을 포함하는 것일 수 있다. 구체적으로는， 상기 수화물은 활성성분 1 몰을 기준으로 물을 약 0.25몰 내지 약 10몰 비로 포함할 수 있으며， 보다 구체적으로는 약 0.5몰， 약 1몰， 약 1.5몰， 약 2몰， 약 2.5몰， 약 3몰， 약 5몰 등을 포함할 수 있다. 본 발명의 ‘용매화물’ 은 아다만탄 유도체， 이의 이성질체 또는 이의 약학적으로 허용가능한 염과 물이 아닌 용매가 분자간 힘으로 결합되어 있는 것으로， 용매를 화학양론적 또는 비화학양론적 양으로 포함할 수 있다. 구체적으로는， 상기 2021/111311 ?01/162020/061350 용매화물은 활성성분 1 몰을 기준으로 용매분자를 약 0.25몰 내지 약 10몰 비로 포함할 수 있으며， 보다 구체적으로는 약 0.5몰， 약 1몰， 약 1.5몰， 약 2몰， 약 2.5몰， 약 3몰， 약 5몰 등으로 포함할 수 있다. 본 발명에서， ”억제제"는 효소의 활성을 차단하거나 감소시키는 화합물을 나타낸다. 억제제는 가역적으로 또는 비가역적으로 결합할 수 있으며， 따라서， 본 용어는 효소의 기질을 사멸시키는 화합물을 포함한다. 억제제는 효소 활성 부위상의 또는 이 근처의 하나 이상의 부위를 변형시킬 수 있거나， 효소상의 다른 곳의 형태 변화를 초래할 수 있다. 아다만탄 유도체 화합물을 포함하는 조성물 , 이의 용도 및 이를 이용한 치료방법 본 발명은 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물을 유효성분으로 포함하는 약학적 조성물을 제공한다. 본 발명은 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물을 유효성분으로 포함하는，
Figure imgf000025_0001
활성 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다. 또한， 본 발명의 아다만탄 유도체， 이의 입체 이성질체 또는 이의 약학적으로 허용가능한 염은
Figure imgf000025_0002
및 ? 뇨2에2) 중 적어도 어느 하나의 활성을 억제할 수 있다.
Figure imgf000025_0003
비정상적인 활성에 의해 유도되는 비정상 2021/111311 ?01/162020/061350 세포 성장 질환으로， 자가면역 질환， 염증성 질환， 골 질환， 대사성 질환， 신경학 및 신경변성 질환， 암， 심혈관 질환， 알레르기 및 천식， 알츠하이머병， 바이러스 질환 및 호르몬 관련 질환으로 이루어지는 군으로부터 선택되는 적어도 하나인 것일 수 있으며， 바람직하게는， 위암， 폐암， 간암， 대장암， 소장암， 췌장암， 뇌암， 뼈암， 흑색종， 유방암， 자궁암， 자궁경부암， 난소암， 두경부암， 갑상선암， 부갑상선암， 신장암， 전립선암， 요도암， 방광암， 중피종 등을 포함한 고형암과 백혈병， 다발성골수종， 림프종 등을 포함한 혈액암으로 이루어진 군으로부터 선택된 어느 하나일 수 있다. 보다 바람직하게는， FAK의 비정상적인 활성에 의해 유도되는 비정상 세포 성장 질환은 침윤성 및 전이성이 강한 삼중음성 유방암， 대장암， 폐암 및 악성 중피종으로 이루어진 군으로부터 선택된 어느 하나일 수 있다. 이외에도
Figure imgf000026_0001
비정상적 기능과 관련된 증상 또는 질환을 포함한다.
Figure imgf000026_0002
질환의 예방 또는 치료를 위한 본 발명의 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물의 용도를 제공한다. 또한 본 발명은 치료학적으로 유효한 양의 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물을 개체에게 투여하는 것을 포함하는 FAK 활성 관련 질환의 예방 또는 치료하는 방법을 제공한다. 본 발명에서 사용되는 용어， “예방” 이란 본 발명에 따른 화합물의 투여에 의해 활성 관련 질환을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다. 본 발명에서 사용되는 용어， “치료” 란 본 발명에 따른 화합물의 투여에 2021/111311 ?01/162020/061350 의해 활성 관련 질환에 대한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다 . 또한， 본 발명은 아다만탄 유도체， 이의 입체 이성질체 또는 이의 약학적으로 허용가능한 염을 개체에 투여하는 단계를 포함하는
Figure imgf000027_0001
의 활성을 억제하는 방법을 제공한다. 본 발명의
Figure imgf000027_0002
관련 질환의 예방 또는 치료 방법은 아다만탄 유도체 화합물， 이의 약학적으로 허용가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물을 투여함으로써， 징후의 발현 전에 질병 그 자체를 다룰 뿐만 아니라， 이의 징후를 저해하거나 피하는 것을 또한 포함한다. 질환의 관리에 있어서， 특정 활성 성분의 예방적 또는 치료학적 용량은 질병 또는 상태의 본성（11 11 ）과 심각도， 그리고 활성 성분이 투여되는 경로에 따라 다양할 것이다. 용량 및 용량의 빈도는 개별 환자의 연령， 체중 및 반응에 따라 다양할 것이다. 적합한 용량 용법은 이러한 인자를 당연히 고려하는 이 분야의 통상의 지식을 가진 자에 의해 쉽게 선택될 수 있다. 또한， 본 발명의 FAK 활성 관련 질환의 예방 또는 치료 방법은 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물과 함께 질환 치료에 도움이 되는 추가적인 활성 제제의 치료학적으로 유효한 양의 투여를 더 포함할 수 있으며， 추가적인 활성제제는 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물과 함께 시너지 효과 또는 보조적 효과를 나타낼 수 있다. 본 발명은
Figure imgf000027_0003
활성 관련 질환의 예방 또는 치료용 약제의 제조를 위한 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물의 용도를 제공하고자 한다. 약제의 제조를 위한 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물은 허용되는 보조제， 희석제， 담체 등을 혼합할 수 있으며， 기타 활성제제와 함께 복합 제제로 제조되어 활성 성분들의 상승 작용을 가질 수 있다. 본 발명의 약학적 조성물은 약학적으로 허용되는 담체를 추가로 포함할 수 있다. 이때， 약학적으로 허용되는 담체는 제제 시에 통상적으로 이용되는 것으로서， 락토스， 텍스트로스， 수크로스， 솔비톨， 만니톨， 전분， 아카시아고무， 인산 칼슘， 알기네이트， 젤라틴， 규산 칼슘， 미세 결정성셀룰로스， 폴리비닐피로리돈， 셀룰로스， 물， 시럽， 메틸 셀룰로스， 메틸히드록시벤조에이트， 프로필 히드록시벤조에이트， 활석， 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나， 이에 한정되는 것은 아니다. 또한， 상기 성분들 이외에 윤활제， 습윤제， 감미제， 향미제， 유화제， 현탁제， 보존제 등을 추가로 포함할 수 있다 . 또한， 본 발병의 약학적 조성물은 세포신호전달 억제제 (cel l signal transduct ion inhibitors) , 유사분열 저해제 (mitosis inhibitors) , 알킬화제 (alkylat ing agents) , 대사길항제 (ant imetabol ites) , 항생제 (ant ibiot ics) , 성장인자 저해제 (growth factor inhibitors) , 세포주기 저해제 (cel l cycle inhibitors) , 토포이소머라아제 저해제 (topoisomerase inhibitors) , 생물학적 반응조절제 (biological react ion modi f iers) , 항호르몬제 (ant i hormonal agents) , 항안드로겐제 (ant i androgen) , 세포 분화/증식/생존 저해제 (cel l di fferent iat ion/prol i ferat ion/survival inhibitors) ,
Figure imgf000028_0001
U apoptosis inducer）로 이루어진 군으로부터 선택된 약제를 추가적으로 포함할 수 있으며， 본 발명의 약학적 조성물을 제제화 하는 경우에는 상기 추가적으로 포함되는 약제와 병용하거나 또는 복합 제제화할 수 있다. 본 발명의 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구투여（예를 들어， 정맥 내， 피하， 복강 내 또는 국소에 적용）할 수 있으며， 투여량은 환자의 상태 및 체중， 질병의 정도， 약물형태， 투여경로 및 시간에 따라 다르지만， 당업자에 의해 적절하게 선택될 수 있다. 본 발명의 약학적 조성물은 치료학적으로 유효한 양으로 투여한다. 본 발명에 있어서， “치료학적으로 유효한 양” 은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 중분한 양을 의미하며， 유효용량 수준은 환자의 질환의 종류， 중증도， 약물의 활성， 약물에 대한 민감도， 투여 시간， 투여 경로 및 배출비율， 치료기간， 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명에 다른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며， 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며， 이는 당업자에 의해 용이하게 결정될 수 있다. 구체적으로 본 발명의 약학적 조성물의 유효량은 환자의 연령， 성별， 상태， 체중， 체내에 활성 성분의 흡수도， 불활성율 및 배설속도， 질병종류， 병용되는 약물에 따라 달라질 수 있으며， 일반적으로는 체중 1
Figure imgf000029_0001
당 0.001 내지 160 1 ， 바람직하게는 0.01 내지 100
Figure imgf000029_0002
또는 격일 투여하거나， 1일 1 내지 3 회로 2021/111311 ?01/162020/061350 나누어 투여할 수 있다. 그러나 투여 경로， 비만의 중증도， 성별， 체중， 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다. 본 발명에서 “개체” 란 질병의 예방 또는 치료가 있어야 하는 대상을 의미하고， 보다 구체적으로는， 인간， 원숭이， 생쥐細0배6）， 개， 고양이， 말， 소 등의 포유류를 의미할 수 있으나， 여기에 한정되는 것은 아니다. 본 발명의 용도， 조성물， 치료 방법에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용되며， 이밖에 본 명세서에서 사용된 용어들과 약어들은 달리 정의되지 않는 한， 그 본래의 의미를 갖는다. 이하， 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다. 실시예
Figure imgf000022_0001
Figure imgf000023_0001
In the present invention, "stereoisomer" includes diastereomers and optical isomers, and optical isomers include not only enantiomers, but also mixtures of enantiomers and racemates. do 2021/111311 - 01/162020/061350 In the present invention, "pharmaceutically acceptable salt" refers to a salt commonly used in the pharmaceutical industry, for example, calcium, potassium, sodium and magnesium, etc. inorganic ions prepared salts, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid, hydroiodic acid and sulfuric acid; Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid acid, ascorbic acid, an organic acid salt prepared with carbonic acid and vanillic acid; sulfonic acid salts prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, ]3-toluenesulfonic acid and naphthalenesulfonic acid; Amino acid salts prepared from glycine, arginine and lysine; and amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine and picoline, etc., but the types of salts implied in the present invention are not limited by these listed salts. The 'hydrate' of the present invention is an adamantane derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof and water, which are bound by a non-covalent intermolecular force, and includes a stoichiometric or non-stoichiometric amount of water. can Specifically, the hydrate may contain water in a ratio of about 0.25 mole to about 10 moles based on 1 mole of the active ingredient, and more specifically, about 0.5 mole, about 1 mole, about 1.5 mole, about 2 mole, about 2.5 moles, about 3 moles, about 5 moles, etc. may be included. The 'solvate' of the present invention is an adamantane derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof and a solvent other than water combined by an intermolecular force, and the solvent is included in a stoichiometric or non-stoichiometric amount can do. Specifically, the 2021/111311 - 01/162020/061350 The solvate may contain solvent molecules in a ratio of about 0.25 to about 10 moles based on 1 mole of the active ingredient, and more specifically, about 0.5 moles, about 1 moles, about 1.5 moles , about 2 moles, about 2.5 moles, about 3 moles, about 5 moles, etc. may be included. In the present invention, "inhibitor" refers to a compound that blocks or reduces the activity of an enzyme. Inhibitors can bind reversibly or irreversibly, therefore, the term includes compounds that kill the substrate of the enzyme. Inhibitors may modify one or more sites on or near the enzyme active site, or may cause a conformational change elsewhere on the enzyme Composition comprising an adamantane derivative compound, its use, and a treatment method using the same Provided is a pharmaceutical composition comprising an adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof as an active ingredient.The present invention provides an adamantane derivative, a pharmaceutically acceptable salt thereof , containing its stereoisomer, its hydrate or solvate as an active ingredient,
Figure imgf000025_0001
Provided is a pharmaceutical composition for preventing or treating an activity-related disease. In addition, the adamantane derivative of the present invention, a stereoisomer or a pharmaceutically acceptable salt thereof
Figure imgf000025_0002
and ? It is possible to inhibit the activity of at least one of 2 and 2) in urine.
Figure imgf000025_0003
Abnormalities induced by abnormal activity 2021/111311 ?01/162020/061350 Cell growth disease, autoimmune disease, inflammatory disease, bone disease, metabolic disease, neurological and neurodegenerative disease, cancer, cardiovascular disease, allergy and asthma, Alzheimer's disease, viral disease and hormone-related It may be at least one selected from the group consisting of diseases, preferably stomach cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, uterine cancer, cervical cancer, ovarian cancer, both It may be any one selected from the group consisting of solid cancers including cervical cancer, thyroid cancer, parathyroid cancer, kidney cancer, prostate cancer, urethral cancer, bladder cancer, mesothelioma, and blood cancer including leukemia, multiple myeloma, lymphoma, and the like. More preferably, the abnormal cell growth disease induced by the abnormal activity of FAK may be any one selected from the group consisting of invasive and metastatic triple-negative breast cancer, colorectal cancer, lung cancer and malignant mesothelioma. Besides
Figure imgf000026_0001
symptoms or diseases associated with abnormal function.
Figure imgf000026_0002
Provided is the use of the adamantane derivative of the present invention, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof for the prevention or treatment of a disease. In addition, the present invention provides a method for preventing or treating a disease related to FAK activity, comprising administering to an individual a therapeutically effective amount of an adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof provides As used herein, the term “prevention” refers to any action that suppresses or delays the onset of an activity-related disease by administration of the compound according to the present invention. As used herein, the term “treatment” refers to the administration of the compound according to the present invention. 2021/111311 ?01/162020/061350 Refers to any action in which symptoms for an active-related disease are improved or changed to a beneficial effect. In addition, the present invention comprises administering to an individual an adamantane derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof
Figure imgf000027_0001
A method for inhibiting the activity of of the present invention
Figure imgf000027_0002
A method for preventing or treating a related disease is by administering an adamantane derivative compound, a pharmaceutically acceptable salt thereof, a stereoisomer, a hydrate or a solvate thereof, not only to treat the disease itself before the onset of symptoms, but also to treat the symptoms It also includes inhibiting or avoiding. In the management of diseases, the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition ( 11 11 ), and the route through which the active ingredient is administered. The dose and frequency of dose will vary with the age, weight and response of the individual patient. A suitable dosage regimen can be readily selected by one of ordinary skill in the art taking these factors into account. In addition, the method for preventing or treating FAK activity-related diseases of the present invention is an adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof together with an additional active agent that is helpful in the treatment of diseases. It may further include administration of a pharmaceutically effective amount, and the additional active agent may exhibit a synergistic or auxiliary effect together with an adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof. . the present invention
Figure imgf000027_0003
Adamantane derivatives, pharmaceutically acceptable salts thereof, stereoisomers thereof, and adamantane derivatives for the preparation of drugs for the prevention or treatment of activity-related diseases It is intended to provide the use of the hydrate or solvate. An adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof for the manufacture of a drug may be mixed with an acceptable adjuvant, a diluent, a carrier, etc., as a complex formulation together with other active agents may be formulated to have a synergistic action of the active ingredients. The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier. At this time, the pharmaceutically acceptable carrier is commonly used in the formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose , polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, etc., but is not limited thereto. In addition, it may further include a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, etc. in addition to the above components. In addition, the pharmaceutical composition of the present invention is cell signal transduction inhibitors (cell signal transduct ion inhibitors), mitosis inhibitors (mitosis inhibitors), alkylating agents (alkylating agents), metabolic antagonists (ant imetabol items), antibiotics (ant ibiot ics) ) , growth factor inhibitors , cell cycle inhibitors , topoisomerase inhibitors , biological reaction modi fiers , anti hormonal agents) , anti androgens , cell differentiation/proliferation/survival inhibitors (cell di fferent iat ion/prol ferat ion/survival inhibitors) ,
Figure imgf000028_0001
U apoptosis inducer) may additionally include a drug selected from the group consisting of, and in the case of formulating the pharmaceutical composition of the present invention, it may be combined or combined with the additionally included drug. The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or locally applied) according to a desired method, and the dosage may vary depending on the patient's condition and weight, and disease. Although it varies depending on the degree, drug form, administration route and time, it may be appropriately selected by those skilled in the art. The pharmaceutical composition of the present invention is administered in a therapeutically effective amount. In the present invention, "therapeutically effective amount" means an amount that is moderate to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type, severity, and drug of the patient. Activity, sensitivity to drugs, administration time, administration route and excretion rate, treatment period, factors including concurrently used drugs, and other factors well-known in the medical field may be determined according to. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple. It is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects in consideration of all of the above factors, which can be easily determined by those skilled in the art. Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, weight, absorption of the active ingredient in the body, inactivation rate and excretion rate, disease type, and drugs used in combination weight 1
Figure imgf000029_0001
0.001 to 160 1 per sugar, preferably 0.01 to 100
Figure imgf000029_0002
Or administered every other day, or 1 to 3 times a day 2021/111311 ?01/162020/061350 Can be administered in divided doses. However, since it may increase or decrease depending on the route of administration, the severity of obesity, sex, weight, age, etc., the dosage is not intended to limit the scope of the present invention in any way. In the present invention, "individual" means a subject that should be prevented or treated for disease, and more specifically, it may refer to mammals such as humans, monkeys, mice, etc. 6), dogs, cats, horses, cattle, etc. However, the present invention is not limited thereto. Unless otherwise defined, the terms and abbreviations used herein have their original meanings unless otherwise defined. Hereinafter, to help the understanding of the present invention, examples will be described in detail. However, the following examples are merely illustrative of the contents of the present invention, and the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art. Example
<실시예 1> 2-（（2-（（4-（（（公· 2 ）- 5 -하이드록시아다만탄- 2 -일）아미노）- 2- 메록시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）-成 3- 다이메틸벤즈아마이드의 제조 （화합물 1） 2021/111311 1^(:1^2020/061350
Figure imgf000031_0001
<Example 1> 2-((2-((4-(((public·2)-5-hydroxyadamantan-2-yl)amino)-2-meroxyphenyl)amino)-5-( Preparation of trifluoromethyl)pyrimidin-4-yl)amino)-produced 3-dimethylbenzamide (Compound 1) 2021/111311 1^(:1^2020/061350
Figure imgf000031_0001
[단계 1] （紅 ）-4-（（3 -메톡시- 4 -나이트로페닐）아미노）아다만탄- 1 -올의 제조
Figure imgf000031_0002
紅 <3 « 4 -아미노아다만탄- 1 -올， 4 -플루오로- 2 -메톡시- 1 -나이트로벤젠， 탄산 포타슘， 다이메틸설폭사이드를 잘 교반하며 5 시간 동안 1201로 가열하였다. 상온으로 식힌 후 잘 교반하며 반응 용액에 물을 가하여 석출시키고， 석출된 고체를 여과하여 얻어냈다. 얻어낸 고체를 컬럼 크로마토그래피로 정제하여 표제 화합물을 얻었다. [Step 1] Preparation of (紅)-4-((3-methoxy-4-nitrophenyl)amino)adamantan-1-ol
Figure imgf000031_0002
紅<3 « 4-aminoadamantan- 1-ol, 4-fluoro-2 -methoxy- 1-nitrobenzene, potassium carbonate, and dimethyl sulfoxide were stirred well and heated to 1201 for 5 hours. After cooling to room temperature and stirring well, water was added to the reaction solution to precipitate, and the precipitated solid was obtained by filtration. The obtained solid was purified by column chromatography to obtain the title compound.
[단계 2] （ <¾75）-4-（（4 -아미노- 3 -메톡시페닐）아미노）아다만탄- 1 -올의 제조
Figure imgf000031_0003
상기 단계 1 에서 제조한 （ ^/ « ^-（（크-메톡시-간- 나이트로페닐）아미노）아다만탄- 1 -올을 에탄올에 녹인 후 10% 팔라듐/탄소 촉매를 넣고 수소 압력 하에서 15 시간 동안 교반하였다. 반응 완료 후 셀라이트에 여과하여 2021/111311 1^(:1^2020/061350 여액을 감압 농축하고 추가 정제 없이 바로 다음 단계에 사용하였다. [Step 2] Preparation of (<¾75)-4-((4-amino-3-methoxyphenyl)amino)adamantan-1-ol
Figure imgf000031_0003
After dissolving the ( ^/ « ^-((K-methoxy-gan-nitrophenyl)amino)adamantan-1-ol prepared in step 1 in ethanol, 10% palladium/carbon catalyst was added thereto, and under hydrogen pressure Stirred for 15 hours. After completion of the reaction, filtered through celite 2021/111311 1^(:1^2020/061350 The filtrate was concentrated under reduced pressure and used directly in the next step without further purification.
[단계 3] （紅 ）-4-（（4-（（4 -클로로- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）- 3 -메톡시페닐）아미노）아다만탄- 1 -올의 제조
Figure imgf000032_0001
[Step 3] (紅)-4-((4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)adamantane- Preparation of 1-ol
Figure imgf000032_0001
1,2 -다이클로로에테인과
Figure imgf000032_0002
혼합용매（1:1）에 2,4 -다이클로로- 5- （트라이플루오로메틸）피리미딘을 녹인 후 이염화 아연을 넣고 상온에서 30분 간 교반하였다. 01로 냉각한 다음 상기 단계 2에서 제조한 （紅＜ 5） -4-（（4 -아미노- 3- 메톡시페닐）아미노）아다만탄- 1 -올을 1,2 -다이클로로에테인과 卜부탄올 혼합용매（1:1）에 녹여 천천히 가하였다. 01 에서 1 시간 교반한 후 다이아이소프로필아민을 가하고 상온에서 15 시간 교반하였다. 반응 용액에 얼음물을 부은 후 다이클로로메테인으로 추출하고 무수 황산 마그네슘으로 건조 후 거르고， 여액을 농축한 후 컬럼 크로마토그래피로 정제하여 표제 화합물을 얻었다. 1,2 -dichloroethane and
Figure imgf000032_0002
2,4-dichloro-5-(trifluoromethyl)pyrimidine was dissolved in a mixed solvent (1:1), zinc dichloride was added, and the mixture was stirred at room temperature for 30 minutes. After cooling to 01, (紅<5) -4-((4-amino-3-methoxyphenyl)amino)adamantan-1-ol prepared in step 2 was mixed with 1,2-dichloroethane It was dissolved in a butanol mixed solvent (1:1) and slowly added. After stirring at 01 for 1 hour, diisopropylamine was added and the mixture was stirred at room temperature for 15 hours. Ice water was poured into the reaction solution, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain the title compound.
[단계 4] 2-（（2-（（4-（（（紅 ）-5 -하이드록시아다만탄- 2 -일）아미노）- 2- 메톡시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᄊ 3- 다이메틸벤즈아마이드의 제조
Figure imgf000032_0003
상기 단계 3 에서 제조한 （ ＜¾?£） -4-（（4-（（4 -클로로- 5-[Step 4] 2-((2-((4-((((紅)-5-hydroxyadamantan-2-yl)amino)-2-methoxyphenyl)amino)-5-(trifluoro Preparation of methyl)pyrimidin-4-yl)amino)- ᄊ 3-dimethylbenzamide
Figure imgf000032_0003
(<¾?£) -4-((4-((4-chloro-5-) prepared in step 3
（트라이플루오로메틸）피리미딘- 2 -일）아미노）- 3 -메톡시페닐）아미노）아다만탄- 1 -올， 2021/111311 ?01/162020/061350(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)adamantan-1-ol; 2021/111311 ?01/162020/061350
2 -아미노-ᄊ 3 -다이메틸벤즈아마이드를 2 -부탄올에 녹인 후 트라이플루오로아세트산을 가하여 5 시간 동안 환류 교반하였다. 상온으로 식힌 후 반응 용액에 증류수를 가하고 아세트산 에틸로 추출하였다. 무수 황산 마그네슘으로 건조 후 여과하고 여 액을 농축한 후 컬럼 크로마토그래피로 정제하여 표제 화합물을 얻었다.
Figure imgf000033_0001
0 ）이3）: 6 8.24 （ 111）， 8.19 （ 111）， 7.38 （（!， I =2-Amino-ᄊ 3-dimethylbenzamide was dissolved in 2-butanol, trifluoroacetic acid was added thereto, and the mixture was stirred under reflux for 5 hours. After cooling to room temperature, distilled water was added to the reaction solution, followed by extraction with ethyl acetate. It was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain the title compound.
Figure imgf000033_0001
0 ) is 3 ): 6 8.24 ( 111), 8.19 ( 111), 7.38 ((!, I =
7.4 ¾， 내）， 7.34 （（!， I = 7.5 ¾， 내）， 7.27 - 7.22 （111, 내）, 6.12 （（1, I = 1.8 페 , 6.04
Figure imgf000033_0002
페 , 5.76
Figure imgf000033_0003
페 , 3.78
Figure imgf000033_0004
예）, 3.44
Figure imgf000033_0005
페 , 2.83 （（1, I =7.4 ¾, within), 7.34 ((!, I = 7.5 ¾, within), 7.27 - 7.22 (111, within), 6.12 ((1, I = 1.8 peso, 6.04)
Figure imgf000033_0002
P , 5.76
Figure imgf000033_0003
P , 3.78
Figure imgf000033_0004
ex), 3.44
Figure imgf000033_0005
Pe , 2.83 （（1, I =
4.6 예）, 2.22 - 2.11 （111, 해）, 1.92 - 1.69 （111, ）, 1.60 - 1.40 （111, 예） 4.6 Example), 2.22 - 2.11 (111, year), 1.92 - 1.69 (111, ), 1.60 - 1.40 (111, example)
<실시예 2 ñ 2-（（2-（（4-（아다만탄- 2 -일아미노）- 2 -메톡시페닐）아미노）- 5-<Example 2 - 2-((2-((4-(adamantan-2-ylamino)-2-methoxyphenyl)amino)-5-
（트라이플루오로메틸）피리미딘- 4 -일）아미노）-成 3 -다이메틸벤즈아마이드의 제조Preparation of (trifluoromethyl)pyrimidin-4-yl)amino)-produced 3-dimethylbenzamide
（화합물 2）
Figure imgf000033_0006
(Compound 2)
Figure imgf000033_0006
[단계 1] 於（3 -메톡시- 4 -나이트로페닐）아다만탄- 2 -아민의 제조
Figure imgf000033_0007
실시 예 1 의 단계 1 에서 <3 « 4 -아미노아다만탄- 1 -올 대신에 아다만탄- 2- 2021/111311 ?01/162020/061350 아민을 사용하여 실시예 1과 동일한 방법으로 표제 화합물을 합성하였다. [Step 1] Preparation of 於(3-methoxy-4-nitrophenyl)adamantan-2-amine
Figure imgf000033_0007
In step 1 of Example 1, <3 « 4 -Adamantane-2- instead of 4-aminoadamantane- 1-ol 2021/111311 -01/162020/061350 The title compound was synthesized in the same manner as in Example 1 using the amine.
［단계 2］ 聲（아다만탄- 2 -일）- 3 -메톡시벤젠- 1,4 -다이아민의 제조
Figure imgf000034_0001
실시예 1 의 단계 2 에서 （ ^/^« ^-（（크-메톡시-간- 나이트로페닐）아미노）아다만탄- 1 -올 대신에 聲（3 -메톡시- 4 -나이트로페닐）아다만탄_ 2 -아민을 사용하여 실시예 1과 동일한 방법으로 표제 화합물을 합성하였다. [Step 2] Preparation of 聲 (adamantan-2-yl)- 3 -methoxybenzene- 1,4-diamine
Figure imgf000034_0001
In step 2 of Example 1, (^/^« ^-((k-methoxy-gan-nitrophenyl)amino)adamantan-1-ol in place of 聲(3-methoxy-4-nitrophenyl) ) The title compound was synthesized in the same manner as in Example 1 using adamantane_ 2-amine.
［단계 3］ 聲 （아다만탄- 2 -일）-聲（4 -클로로- 5-[Step 3] 聲 (adamantan-2-yl)-聲 (4-chloro-5-
（트라이플루오로메틸）피리미딘- 2 -일）-2 -메톡시벤젠- 1， 4 -다이아민의 제조
Figure imgf000034_0002
실시예 1 의 단계 3 에서 （ « - -（（간 -아미노- 3_ 메톡시페닐）아미노）아다만탄- 1 -올 대신에 聲（아다만탄- 2 -일）- 3 -메톡시벤젠- 1,4- 다이아민을 사용하여 실시예 1과 동일한 방법으로 표제 화합물을 합성하였다. Preparation of (trifluoromethyl)pyrimidin-2-yl)-2-methoxybenzene-1,4-diamine
Figure imgf000034_0002
In step 3 of Example 1 ( «--((liver-amino-3_ methoxyphenyl)amino)adamantan-1-ol instead of 聲(adamantan-2-yl)-3 -methoxybenzene- The title compound was synthesized in the same manner as in Example 1 using 1,4-diamine.
［단계 4］ 2-（（2-（（4-（아다만탄- 2 -일）아미노）- 2 -메톡시페닐）아미노）- 5-[Step 4] 2-((2-((4-(adamantan-2-yl)amino)-2-methoxyphenyl)amino)-5-
（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᄊ 3 -다이메틸벤즈아마이드의 제조
Figure imgf000034_0003
실시예 1 의 단계 4 에서 （紅 ） -4-（（4-（（4 -클로로- 5- 2021/111311 ?01/162020/061350 Preparation of (trifluoromethyl)pyrimidin-4-yl)amino)-ᄊ 3-dimethylbenzamide
Figure imgf000034_0003
In step 4 of Example 1 (紅) -4- ((4- ((4-chloro-5- 2021/111311 ?01/162020/061350
（트라이플루오로메틸）피 리미딘- 2 -일）아미노）- 3 -메톡시페닐）아미노）아다만탄- 1 -올 대신에 聲（아다만탄- 2 -일）-^（4 -클로로- 5-（트라이플루오로메틸）피 리미딘- 2 -일）-2 - 메특시벤젠- 1，4 -다이아민을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . (Trifluoromethyl)pyrimidin-2-yl)amino)-3 -methoxyphenyl)amino)adamantan-1-ol instead of 聲(adamantan-2-yl)-^(4-chloro The title compound was synthesized in the same manner as in Example 1 using -5-(trifluoromethyl)pyrimidin-2-yl)-2-methoxybenzene-1,4-diamine.
¾ » （400 ， 0-（16）: 6 9.10 ， 페， 8.30 - 8.25 （111, 페 , 8.20 （ 내）, 7.91 （ 내）, 7.39 （（!, I = 7.7 ¾ , 내）, 7.34 （（!, I = 6.9 ¾ , 내）, 7.25 - 7.20 （111, 내）, 7.01 （加 내）, 6.32 （ 내）, 5.40 （加 내）, 3.63 （ 예）, 3.43 - 3.38 （111, 내）, 2.69 （（1, I = 4.5 ¾ , 예）, 2.15 - 2.00 （111, 해）, 1.94 - 1.69 （111, 911）， 1.51 - 1.45 （111, ¾） ¾ » （400 ， 0-（1 6 ）: 6 9.10 , pe, 8.30 - 8.25 （111, pe , 8.20 (in), 7.91 (in), 7.39 ((!, I = 7.7 ¾ , in), 7.34 ( (!, I = 6.9 ¾ , within), 7.25 - 7.20 (111, within), 7.01 (within), 6.32 (within), 5.40 (within), 3.63 (eg), 3.43 - 3.38 (within 111, within) , 2.69 ((1, I = 4.5 ¾ , eg), 2.15 - 2.00 (111, year), 1.94 - 1.69 (111, 911), 1.51 - 1.45 (111, ¾)
<실시예 3> 2-（（2-（（4-（4-（아다만탄- 2 -일）피페라진- 1 -일）- 2- 메특시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）-成 3- 다이메틸벤즈아마이드의 제조 （화합물 3）
Figure imgf000035_0001
2021/111311 ?01/162020/061350 실시 예 1 의 단계 1 에서 <3 « 4 -아미노아다만탄- 1 -올 대신에 피페라진을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다. <Example 3> 2-((2-((4-(4-(adamantane-2-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-(trifluoro Preparation of methyl)pyrimidin-4-yl)amino)-produced 3-dimethylbenzamide (Compound 3)
Figure imgf000035_0001
2021/111311 -01/162020/061350 In step 1 of Example 1, the title compound was synthesized in the same manner as in Example 1 using piperazine instead of <3 « 4-aminoadamantan-1-ol.
[단계 2] 1-（아다만탄- 2 -일）- 4-（3 -메톡시- 4 -나이트로페닐）피페라진의 제조
Figure imgf000036_0001
상기 단계 1 에서 제조한 1-（3 -메톡시- 4 -나이트로페닐）피페라진， 아다만탄_ 2 -온， 트라이아세톡시소듐보로하이드라이드， 테트라하이드로퓨란， 아세트산을 상온에서 15 시간 동안 교반하였다. 반응 용액에 얼음물을 부은 후 아세트산 에틸로 추출하고 무수 황산 마그네슘으로 건조 후 거르고， 여 액을 농축한 후 컬럼 크로마토그래피로 정제하여 표제 화합물을 얻었다. [Step 2] Preparation of 1-(adamantan-2-yl)- 4-(3-methoxy-4-nitrophenyl)piperazine
Figure imgf000036_0001
1-(3-methoxy-4-nitrophenyl)piperazine, adamantane_2-one, triacetoxysodium borohydride, tetrahydrofuran, and acetic acid prepared in step 1 were heated at room temperature for 15 hours. stirred for a while. Ice water was poured into the reaction solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain the title compound.
[단계 3] 4-（4-（아다만탄- 2 -일）피페라진- 1 -일）- 2 -메톡시아닐린의 제조
Figure imgf000036_0002
실시 예 1 의 단계 2 에서 （ /^^ ^-（ -메톡시-간- 나이트로페닐）아미노）아다만탄- 1 -올 대신에 1-（아다만탄- 2 -일）- 4-（3 -메톡시- 4- 나이트로페닐）피페라진을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다. [Step 3] Preparation of 4-(4-(adamantan-2-yl)piperazin-1-yl)-2-methoxyaniline
Figure imgf000036_0002
In step 2 of Example 1 (/^^ ^-(-methoxy-gan-nitrophenyl)amino)adamantan-1-ol instead of 1-(adamantan-2-yl)-4-( The title compound was synthesized in the same manner as in Example 1 using 3-methoxy-4-nitrophenyl)piperazine.
[단계 4] 聲（4-（4-（아다만탄- 2 -일）피페라진- 1 -일）- 2 -메톡시페닐- 4 -클로로_ 5-（트라이플루오로메틸）피리미딘- 2 -아민의 제조
Figure imgf000037_0001
실시 예 1 의 단계 3 에서 （ « - -（（간 -아미노- 3_ 메톡시페닐 ）아미노）아다만탄- 1 -올 대신에 4-（4-（아다만탄- 2 -일）피페라진- 1 -일）- 2- 메톡시아닐린을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다. [Step 4] 聲（4-(4-(adamantan-2-yl)piperazin- 1-yl)-2 -methoxyphenyl-4 -chloro_ Preparation of 5-(trifluoromethyl)pyrimidin-2-amine
Figure imgf000037_0001
In step 3 of Example 1, 4-(4-(adamantan-2-yl)piperazine- instead of ( «--((liver-amino-3_methoxyphenyl)amino)adamantan-1-ol) 1-yl)- The title compound was synthesized in the same manner as in Example 1 using 2-methoxyaniline.
[단계 5] 2-（（2-（（4-（4-（아다만탄- 2 -일）피페라진- 1 -일）- 2- 메톡시페닐 ）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᄊ 3- 다이메틸벤즈아마이드의 제조
Figure imgf000037_0002
실시 예 1 의 단계 4 에서 （紅 s） -4-（（4-（（4 -클로로- 5-[Step 5] 2-((2-((4-(4-(adamantan-2-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-(trifluoromethyl ）Pyrimidin-4-yl)amino)- ᄊ Preparation of 3-dimethylbenzamide
Figure imgf000037_0002
In step 4 of Example 1 (紅 s) -4- ((4- ((4-chloro-5-
（트라이플루오로메틸）피리미딘- 2 -일）아미노）- 3 -메톡시페닐）아미노）아다만탄- 1-올 대신에 聲（4-（4-（아다만탄- 2 -일）피페라진- 1-일）- 2 -메톡시페닐- 4 -클로로- 5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)adamantan-1-ol instead of 聲(4-(4-(adamantan-2-yl)pipeline) Razin- 1-yl)- 2 -methoxyphenyl-4 -chloro-5-
（트라이플루오로메틸）피리미딘- 2 -아민을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다. The title compound was synthesized in the same manner as in Example 1 using (trifluoromethyl)pyrimidin-2-amine.
¾ NMR （400 MHz , CDCb）: 6 8.26 （s , 2H, over lapped）, 7.41 （d, J = 7.3 Hz , 1H）, 7.34 （d, J = 7.5 Hz , 1H）, 7.31 - 7.26 （m, 1H）, 6.47 （d, J = 2.0 Hz , 2021/111311 ?01/162020/061350 페 , 6.09 （加 페 , 6.00
Figure imgf000038_0001
페 , 3.82 예）, 3.09 （111, , 2.84 （（1, / =¾ NMR (400 MHz , CDCb): 6 8.26 (s , 2H, over lapped), 7.41 (d, J = 7.3 Hz , 1H), 7.34 (d, J = 7.5 Hz , 1H), 7.31 - 7.26 (m, 1H), 6.47 (d, J = 2.0 Hz , 2021/111311 ?01/162020/061350 Pe, 6.09 （加 Pe, 6.00
Figure imgf000038_0001
Pe , 3.82 ex), 3.09 (111, , 2.84 ((1, / =)
4.8 예）, 2.61 （111, 태）, 2.21 （ 해）, 2.19 - 2.10 （111, 래）, 1.96 - 1.82 （111, 태）, 1.76 - 1.65 （111, 해）, 1.54 - 1.39 （111, ¾） 4.8 Ex), 2.61 (111, Tae), 2.21 (Sun), 2.19 - 2.10 (111, Ra), 1.96 - 1.82 (111, Tae), 1.76 - 1.65 (111, Year), 1.54 - 1.39 (111, ¾ )
<실시예 4> 2-（（2-（（4-（4-（（ /¾05）-5 -하이드록시아다만탄- 2 -일）피페라진- 1- 일）-2 -메톡시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）-/ V, 3- 다이메틸벤즈아마이드의 제조 （화합물 4）
Figure imgf000038_0002
<Example 4> 2-((2-((4-(4-(( /¾05)-5-hydroxyadamantan-2-yl)piperazin-1-yl)-2 -methoxyphenyl) Amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)- / V, 3- dimethylbenzamide preparation (Compound 4)
Figure imgf000038_0002
[단계 1] （紅 ）-4-（4-（3 -메톡시- 4 -나이트로페닐）피페라진- 1- 일）아다만탄- 1 -올의 제조
Figure imgf000038_0003
실시 예 3 의 단계 2 에서 아다만탄- 2 -온 대신에 5 -하이드록시아다만탄- 2- 온을 사용하여 실시 예 3 과 동일한 방법으로 표제 화합물을 합성하였다. [Step 1] Preparation of (紅)-4-(4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)adamantan-1-ol
Figure imgf000038_0003
In step 2 of Example 3, the title compound was synthesized in the same manner as in Example 3 using 5-hydroxyadamantan-2-one instead of adamantan-2-one.
[단계 2] （ 5）-4-（4-（4 -아미노- 3 -메톡시페닐）피페라진- 1 -일）아다만탄_[Step 2] (5)-4-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)adamantane_
1 -올의 제조 2021/111311 ?01/162020/061350
Figure imgf000039_0001
실시 예 1 의 단계 2 에서 （ ^/^« ^-（（크-메톡시 -간- 나이트로페닐）아미노）아다만탄- 1 -올 대신에 （紅 ）-4-（4-（3 -메톡시 - 4- 나이트로페닐）피페라진- 1 -일）아다만탄- 1 -올을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . Preparation of 1-ol 2021/111311 ?01/162020/061350
Figure imgf000039_0001
In step 2 of Example 1, (^/^« ^-((k-methoxy-gan-nitrophenyl)amino)adamantan-1-ol instead of (紅)-4-(4-(3- The title compound was synthesized in the same manner as in Example 1 using methoxy-4-nitrophenyl)piperazin-1-yl)adamantan-1-ol.
[단계 3] （紅 ）-4-（4-（4-（（4 -클로로- 5-（트라이플루오로메틸）피 리미딘- 2- 일）아미노）- 3 -메톡시페닐）피페라진- 1 -일）아다만탄- 1 -올의 제조
Figure imgf000039_0002
실시 예 1 의 단계 3 에서 （ « - -（（간 -아미노- 3_ 메톡시페닐）아미노）아다만탄- 1 -올 대신에 （紅 ） -4-（4-（4 -아미노- 3- 메톡시페닐）피페라진- 1 -일）아다만탄- 1 -올을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . [Step 3] (紅)-4-(4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine- 1-day) Preparation of adamantane-1-ol
Figure imgf000039_0002
In step 3 of Example 1, ( «--((liver-amino-3_ methoxyphenyl)amino)adamantan-1-ol instead of (紅)-4-(4-(4-amino-3-methyl) The title compound was synthesized in the same manner as in Example 1 using oxyphenyl)piperazin-1-yl)adamantan-1-ol.
[단계 4] 2-（（2-（（4-（4-（（紅 5）-5 -하이드록시아다만탄- 2 -일）피페라진- 1- 일）-2 -메톡시페닐）아미노）- 5-（트라이플루오로메틸）피 리미딘- 4 -일）아미노）- ᄊ 3 - 다이메틸벤즈아마이드의 제조
Figure imgf000040_0001
[Step 4] 2-((2-((4-(4-((紅 5)-5-hydroxyadamantan-2-yl)piperazin-1-yl)-2-methoxyphenyl)amino )- 5- (trifluoromethyl) pyrimidin-4-yl) amino) - ᄊ 3 - Preparation of dimethylbenzamide
Figure imgf000040_0001
(트라이플루오로메틸 )피리미딘-2-일 )아미노)-3 -메톡시페닐 )아미노)아다만탄-1-올 대신에 (紅 s)-4-(4-(4-((4 -클로로-5-(트라이플루오로메틸 )피리미딘-2- 일 )아미노)-3 -메톡시페닐 )피페라진-1-일 )아다만탄-1-올을 사용하여 실시 예 1과 동일한 방법으로 표제 화합물을 합성하였다. (trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)adamantan-1-ol instead of (紅s)-4-(4-(4-((4-) Chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)adamantan-1-ol in the same manner as in Example 1 The title compound was synthesized.
¾ NMR (400 MHz,CDCI3)： 68.26 (s,2H,overlapped),7.41 (d, J = 7.3 Hz, 1H),7.34 (d, J = 7.5 Hz, 1H), 7.31 - 7.26 (m, 1H), 6.47 (d, J = 2.0 Hz, 1H), 6.09 (br s, 1H),6.00 (s, 1H), 3.82 (s,3H), 3.09 (m,4H), 2.84 (d, J = 4.8 Hz,3H),2.61 (m,4H),2.32 - 2.26 (m, 1H),2.21 (s,3H),2.14 - 1.98 (m, 태), 1.81 - 1.59 (111,仰), 1.42 - 1.24 (111,예) ¾ NMR (400 MHz,CDCI3): 68.26 (s,2H,overlapped),7.41 (d, J = 7.3 Hz, 1H),7.34 (d, J = 7.5 Hz, 1H), 7.31 - 7.26 (m, 1H) , 6.47 (d, J = 2.0 Hz, 1H), 6.09 (br s, 1H), 6.00 (s, 1H), 3.82 (s,3H), 3.09 (m,4H), 2.84 (d, J = 4.8 Hz) ,3H),2.61 (m,4H),2.32 - 2.26 (m, 1H),2.21 (s,3H),2.14 - 1.98 (m, Tae), 1.81 - 1.59 (111,仰), 1.42 - 1.24 (111 ,Yes)
<실시예 5> 2-（（2-（（4-（4-（（ 5）-5-하이드록시아다만탄-2-일）피페라진-1_ 일）-2 -메톡시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᆻ 3- 다이메틸벤즈아마이드의 제조 （화합물 5） 2021/111311 1^(:1^2020/061350
Figure imgf000041_0001
<Example 5> 2-((2-((4-(4-((5)-5-hydroxyadamantan-2-yl)piperazin-1_yl)-2-methoxyphenyl)amino) - Preparation of 5-(trifluoromethyl)pyrimidin-4-yl)amino)- ᆻ3-dimethylbenzamide (Compound 5) 2021/111311 1^(:1^2020/061350
Figure imgf000041_0001
[단계 1] （ ）-4-（4-（3 -메톡시- 4 -나이트로페닐）피페라진- 1 -일）아다만탄-[Step 1] ( )-4-(4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)adamantane-
1 -올의 제조
Figure imgf000041_0002
실시 예 3 의 단계 2 에서 아다만탄- 2 -온 대신에 5 -하이드록시아다만탄- 2 - 온을 사용하여 실시 예 3 과 동일한 방법으로 표제 화합물을 합성하였다. Preparation of 1-ol
Figure imgf000041_0002
In step 2 of Example 3, the title compound was synthesized in the same manner as in Example 3 using 5-hydroxyadamantan-2-one instead of adamantan-2-one.
[단계 2] （ 5）-4-（4-（4 -아미노- 3 -메톡시페닐）피페라진- 1 -일）아다만탄- 1 - 올의 제조
Figure imgf000041_0003
실시 예 1 의 단계 2 에서 （ ^/?50-4-（（3 -메톡시- 4- 나이트로페닐）아미노）아다만탄- 1 -올 대신에 （ 5）-4-（4-（3 -메톡시- 4 - 나이트로페닐）피페라진- 1 -일）아다만탄- 1 -올을 사용하여 실시 예 1 과 동일한 2021/111311 ?01/162020/061350 방법으로 표제 화합물을 합성하였다 . [Step 2] Preparation of (5)-4-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)adamantan-1-ol
Figure imgf000041_0003
In step 2 of Example 1 (^/?50-4-((3-methoxy-4-nitrophenyl)amino)adamantan-1-ol instead of (5)-4-(4-(3) -Methoxy-4-nitrophenyl)piperazin-1-yl)adamantan-1-ol using the same as in Example 1 The title compound was synthesized by the method 2021/111311 -01/162020/061350.
[단계 3] （ ）-4-（4-（4-（（4 -클로로- 5-（트라이플루오로메틸）피 리미딘- 2- 일 ）아미노）- 3 -메톡시페닐）피페라진- 1 -일）아다만탄- 1 -올의 제조
Figure imgf000042_0001
실시 예 1 의 단계 3 에서 （ « - -（（간 -아미노- 3_ 메톡시페닐 ）아미노）아다만탄- 1 -올 대신에 （ 5）-4-（4-（4 -아미노- 3- 메톡시페닐 ）피페라진- 1 -일）아다만탄- 1 -올을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . [Step 3] ( )-4-(4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1 -Japanese) Preparation of adamantane- 1-ol
Figure imgf000042_0001
In step 3 of Example 1 ( «--((liver-amino-3_ methoxyphenyl)amino)adamantan-1-ol instead of ( 5 )-4-(4-(4-amino-3-methyl The title compound was synthesized in the same manner as in Example 1 using oxyphenyl)piperazin-1-yl)adamantan-1-ol.
[단계 4] 2-（（2-（（4-（4-（（ 5）-5-하이드록시아다만탄-2-일）피페라진-1_ 일 ）-2 -메톡시페닐）아미노）- 5-（트라이플루오로메틸）피 리미딘- 4 -일）아미노）- ᄊ 3 - 다이메틸벤즈아마이드의 제조
Figure imgf000042_0002
실시 예 1 의 단계 4 에서 （紅 ） -4-（（4-（（4 -클로로- 5-[Step 4] 2-((2-((4-(4-((5)-5-hydroxyadamantan-2-yl)piperazin-1_yl)-2 -methoxyphenyl)amino)- Preparation of 5-(trifluoromethyl)pyrimidin-4-yl)amino)-ᄊ 3-dimethylbenzamide
Figure imgf000042_0002
In step 4 of Example 1, (紅)-4-((4-((4-chloro-5-
（트라이플루오로메틸）피 리미딘- 2 -일）아미노）- 3 -메톡시페닐）아미노）아다만탄- 1 -올 대신에 （ ）-4-（4-（4-（（4 -클로로- 5-（트라이플루오로메틸）피 리미딘- 2 -일）아미노）_ 3 -메톡시페닐）피페라진- 1 -일）아다만탄- 1 -올을 사용하여 실시 예 1 과 동일한 2021/111311 ?01/162020/061350 방법으로 표제 화합물을 합성하였다. (trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)adamantan-1-ol instead of ( )-4-(4-(4-((4-chloro) - 5-(trifluoromethyl)pyrimidin-2-yl)amino)_3-methoxyphenyl)piperazin-1-yl)adamantan-1-ol The title compound was synthesized by the method 2021/111311 -01/162020/061350.
¾ » （400 , 0犯13）: 6 8.26 （
Figure imgf000043_0001
7.41 （（!， /= 7.3 ¾ ， 내）， 7.34 （（!， I = 7.5 ¾， 내）， 7.31 - 7.26 （111, 내）, 6.47 （（1, I = 2.0
Figure imgf000043_0002
페, 6.09 （加 페, 6.00
Figure imgf000043_0003
페, 3.82
Figure imgf000043_0004
예）, 3.09 （111, , 2.84 （（1, I =¾ » （400 , 0犯1 3 ）: 6 8.26 （
Figure imgf000043_0001
7.41 ((!, /= 7.3 ¾ , within), 7.34 ((!, I = 7.5 ¾, within), 7.31 - 7.26 (111, within), 6.47 ((1, I = 2.0)
Figure imgf000043_0002
Pe, 6.09 (加 Pe, 6.00)
Figure imgf000043_0003
P, 3.82
Figure imgf000043_0004
ex), 3.09 (111, , 2.84 ((1, I =
4.8 예）, 2.61 （111, 태）, 2.33 - 2.25 （111, 내）, 2.21 （ 예）, 2.13 - 1.97 （111, 태 ）, 1.82 - 1.60 （111, 해）, 1.41 - 1.23 （111, 예） 4.8 Yes), 2.61 (111, Tae), 2.33 - 2.25 (111, In), 2.21 (Ex), 2.13 - 1.97 (111, Tae), 1.82 - 1.60 (111, Year), 1.41 - 1.23 (111, Yes) )
<실시예 6> 2-（（2-（（4-（（1-（아다만탄- 2 -일）피페리딘- 4 -일）아미노）- 2- 메록시페닐 ）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ; 3- 다이메틸벤즈아마이드의 제조 （화합물 6）
Figure imgf000043_0005
<Example 6> 2-((2-((4-((1-(adamantan-2-yl)piperidin-4-yl)amino)-2-meroxyphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)amino)-; 3- Preparation of dimethylbenzamide (Compound 6)
Figure imgf000043_0005
[단계 1] 4-（（3 -메톡시- 4 -나이트로페닐）아미노）피페리딘- 1 -카복실산 此/ - 부틸의 제조
Figure imgf000043_0006
실시예 1 의 단계 1 에서 ' <3 « 4 -아미노아다만탄- 1 -올 대신에 4 - 아미노피페 리딘- 1 -카복실산 此/ -부틸을사용하여 실시예 1과동일한방법으로표제 화합물을 합성하였다. 2021/111311 1^(:1^2020/061350[Step 1] Preparation of 4-((3-methoxy-4-nitrophenyl)amino)piperidine-1-carboxylic acid 此/-butyl
Figure imgf000043_0006
In step 1 of Example 1, the title compound was synthesized in the same manner as in Example 1 using '<3 « 4-aminoadamantan-1-ol instead of 4-aminopiperidine-1-carboxylic acid 此/-butyl. did. 2021/111311 1^(:1^2020/061350
[단계 2] 聲（3 -메톡시- 4 -나이트로페닐）피페리딘- 4 -아민의 제조
Figure imgf000044_0001
상기 단계 1 에서 제조한 4-（（3 -메톡시- 4 -나이트로페닐）아미노）피페리딘- 1- 카복실산 此/ -부틸을 다이클로로메테인에 녹인 후 트라이플루오로아세트산을 가한 다음 상온에서 3 시간 교반하였다. 반응 완료 후 반응 용액에 증류수를 가하고 다이클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조 후 여과하고 여액을 농축한 후 컬럼 크로마토그래피로 정제하여 표제 화합물을 얻었다. [Step 2] Preparation of 聲(3-methoxy-4-nitrophenyl)piperidin-4-amine
Figure imgf000044_0001
4-((3-Methoxy-4-nitrophenyl)amino)piperidine-1-carboxylic acid 此/-butyl prepared in step 1 was dissolved in dichloromethane, trifluoroacetic acid was added thereto, and then at room temperature was stirred for 3 hours. After completion of the reaction, distilled water was added to the reaction solution, followed by extraction with dichloromethane. It was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain the title compound.
[단계 3] 1-（아다만탄- 2 -일）-聲（3 -메톡시- 4 -나이트로페닐）피페리딘- 4- 아민의 제조
Figure imgf000044_0002
실시예 3의 단계 2에서 1-（3 -메톡시- 4 -나이트로페닐）피페라진 대신에 （3 -메톡시- 4 -나이트로페닐）피페리딘- 4 -아민을 사용하여 실시예 3 과 동일한 방법으로 표제 화합물을 합성하였다. [Step 3] Preparation of 1-(adamantan-2-yl)-聲(3-methoxy-4-nitrophenyl)piperidin-4-amine
Figure imgf000044_0002
Example 3 using (3-methoxy-4-nitrophenyl)piperidin-4-amine instead of 1-(3-methoxy-4-nitrophenyl)piperazine in step 2 of Example 3 The title compound was synthesized in the same manner as described above.
[단계 4] 聲（1-（아다만탄- 2 -일）피페리딘- 4 -일）- 3 -메톡시벤젠- 1,4- 다이아민의 제조
Figure imgf000044_0003
2021/111311 1^(:1^2020/061350 실시 예 1 의 단계 2 에서 （ ^/^« ^-（（크-메톡시 -간- 나이트로 페닐）아미노）아다만탄- 1 -올 대신에 1-（아다만탄- 2 -일）-聲（3 -메톡시 - 4- 나이트로 페닐）피페리딘- 4 -아민을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . [Step 4] Preparation of 聲(1-(adamantan-2-yl)piperidin-4-yl)-3-methoxybenzene-1,4-diamine
Figure imgf000044_0003
2021/111311 1^(:1^2020/061350 In step 2 of Example 1 ( ^/^« ^-((K-methoxy-gan-nitrophenyl)amino)adamantan- 1-ol instead of The title compound was synthesized in the same manner as in Example 1 using 1-(adamantan-2-yl)-聲(3-methoxy-4-nitrophenyl)piperidin-4-amine.
［단계 5］ 聲（1-（아다만탄- 2 -일）피페리딘- 4 -일）-聲（4 -클로로- 5-[Step 5] 聲（1-(adamantan-2-yl)piperidin-4-yl)-聲（4-chloro-5-
（트라이플루오로메틸）피 리미딘- 2 -일）-2 -메톡시벤젠- 1， 4 -다이아민의 제조
Figure imgf000045_0001
메톡시페닐）아미노）아다만탄- 1 -올 대신에 聲（1-（아다만탄- 2 -일）피페리딘- 4 -일）- 3- 메특시벤젠- 1，4 -다이아민을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . Preparation of (trifluoromethyl)pyrimidin-2-yl)-2 -methoxybenzene-1,4-diamine
Figure imgf000045_0001
Replace methoxyphenyl)amino)adamantan-1-ol with 聲(1-(adamantan-2-yl)piperidin-4-yl)-3-methoxybenzene-1,4-diamine The title compound was synthesized in the same manner as in Example 1.
［단계 6］ 2-（（2-（（4-（（1-（아다만탄- 2 -일）피페리딘- 4 -일）아미노）- 2- 메톡시페닐）아미노）- 5-（트라이플루오로메틸）피 리미딘- 4 -일）아미노）- ᄊ 3- 다이 메틸벤즈아마이드의 제조
Figure imgf000045_0002
실시 예 1 의 단계 4 에서 （紅 5） -4-（（4-（（4 -클로로- 5-[Step 6] 2-((2-((4-((1-(adamantan-2-yl)piperidin-4-yl)amino)-2-methoxyphenyl)amino)-5-( Preparation of trifluoromethyl)pyrimidin-4-yl)amino)- ᄊ 3-dimethylbenzamide
Figure imgf000045_0002
In step 4 of Example 1 (紅 5) -4- ((4- ((4-chloro-5-
（트라이플루오로메틸）피 리미딘- 2 -일）아미노）- 3 -메톡시페닐）아미노）아다만탄- 1 -올 대신에 聲（1-（아다만탄- 2 -일）피페리딘- 4 -일）-聲（ 4 -클로로- 5- 2021/111311 ?01/162020/061350(Trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)adamantan-1-ol instead of 聲(1-(adamantan-2-yl)piperidine - 4-day)-聲（ 4-chloro-5- 2021/111311 ?01/162020/061350
（트라이플루오로메틸）피리미딘- 2 -일）-2 -메톡시벤젠- 1 4 -다이아민을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다.
Figure imgf000046_0001
6 8.25 （ 111）， 8.13 （加 111）， 7.41 - 7.32The title compound was synthesized in the same manner as in Example 1 using (trifluoromethyl)pyrimidin-2-yl)-2 -methoxybenzene- 14-diamine.
Figure imgf000046_0001
6 8.25 ( 111), 8.13 (加 111), 7.41 - 7.32
（111, 래）, 7.29 - 7.24 （111, 내）, 6.13 （（!, / = 2.3 ¾ , 내）, 5.97 （加 내）, 3.78(111, lower), 7.29 - 7.24 (111, within), 6.13 ((!, / = 2.3 ¾ , within), 5.97 (within 加), 3.78
（ 예）, 3.06 - 2.95 （111, 래）, 2.84 （（!, I = 4.8 ¾ , 예）, 2.21 （ 예）, 2.12 -(Example), 3.06 - 2.95 (111, lower), 2.84 ((!, I = 4.8 ¾ , Yes), 2.21 (Example), 2.12 -
1.92 （111, ）, 1.90 - 1.75 （111, 해）, 1.74 - 1.62 （111, 해）, 1.47 - 1.35 （111, 태） 1.92 (111, ), 1.90 - 1.75 (111, year), 1.74 - 1.62 (111, year), 1.47 - 1.35 (111, year)
<실시예 7> 2-（（2-（（4-（（1-（（ /_2/25）_5 -하이드록시아다만탄- 2 -일）피페리딘-<Example 7> 2-((2-((4-((1-(( /_2/25) _5 -hydroxyadamantan-2-yl)piperidine-
4 -일）아미노）- 2 -메특시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4- 일）아미노）-成 3 -다이메틸벤즈아마이드의 제조 （화합물 7）
Figure imgf000046_0002
Preparation of 4-yl)amino)-2 -methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-produced 3-dimethylbenzamide (Compound 7)
Figure imgf000046_0002
[단계 1] （ «）-4-（4-（（3 -메톡시- 4 -나이트로페닐）아미노）피페리딘- 1- 일）아다만탄- 1 -올의 제조
Figure imgf000046_0003
실시 예 6 의 단계 3 에서 아다만탄- 2 -온 대신에 5 -하이드록시아다만탄- 2- 온을 사용하여 실시 예 6 과 동일한 방법으로 표제 화합물을 합성하였다. [Step 1] Preparation of ( «)-4-(4-((3-methoxy-4-nitrophenyl)amino)piperidin-1-yl)adamantan-1-ol
Figure imgf000046_0003
In step 3 of Example 6, the title compound was synthesized in the same manner as in Example 6 using 5-hydroxyadamantan-2-one instead of adamantan-2-one.
[단계 2] （ « ）-4-（4-（（4 -아미노- 3 -메톡시페닐）아미노）피페리딘- 1- 2021/111311 1^(:1^2020/061350 일）아다만탄- 1 -올의 제조
Figure imgf000047_0001
실시 예 1 의 단계 2 에서 （ ^/^« ^-（（크-메톡시 -간- 나이트로페닐）아미노）아다만탄- 1 -올 대신에 （ ＜ ）-4-（4-（（3 -메톡시 - 4- 나이트로페닐）아미노）피페리딘- 1 -일）아다만탄- 1 -올을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . [Step 2] ( « )-4-(4-((4-amino-3-methoxyphenyl)amino)piperidine-1- 2021/111311 1^(:1^2020/061350 days) Production of adamantane- 1-ol
Figure imgf000047_0001
In step 2 of Example 1 ( ^/^« ^-((k-methoxy-gan-nitrophenyl)amino)adamantan-1-ol instead of (< )-4-(4-((3) The title compound was synthesized in the same manner as in Example 1 using -methoxy-4-nitrophenyl)amino)piperidin-1-yl)adamantan-1-ol.
[단계 3] （ ＜ ）-4-（4-（（4-（（4 -클로로- 5-（트라이플루오로메틸）피 리미딘_ 2 -일）아미노）- 3 -메톡시페닐）아미노）피페리딘- 1 -일）아다만탄- 1 -올의 제조
Figure imgf000047_0002
메톡시페닐）아미노）아다만탄- 1 -올 대신에 (亡/ <¾?£) _4_(4_( (4_。1니］ 1노- 3_ 메톡시페닐）아미노）피페리딘- 1 -일）아다만탄- 1 -올을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . [Step 3] ( < )-4-(4-((4-((4-chloro-5-(trifluoromethyl)pyrimidin_2-yl)amino)-3-methoxyphenyl)amino) Preparation of piperidin-1-yl)adamantan-1-ol
Figure imgf000047_0002
In place of methoxyphenyl)amino)adamantan-1-ol (亡/ <¾? £) _4_(4_((4_.1ni] 1-no-3_ methoxyphenyl)amino)piperidin-1-yl ) The title compound was synthesized in the same manner as in Example 1 using adamantan-1-ol.
[단계 4] 2-（（2-（（4-（（1-（（紅 5）-5 -하이드록시아다만탄- 2 -일）피페리딘- 4- 일）아미노）- 2 -메톡시페닐）아미노）- 5-（트라이플루오로메틸）피 리미딘- 4 -일）아미노）_ ᄊ 3 -다이메틸벤즈아마이드의 제조 2021/111311 ?01/162020/061350
Figure imgf000048_0001
실시 예 1 의 단계 4 에서 （紅 5） -4-（（4-（（4 -클로로- 5-[Step 4] 2-((2-((4-((1-((紅 5)-5-hydroxyadamantan-2-yl)piperidin-4-yl)amino)-2-methyl Preparation of oxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)_a 3-dimethylbenzamide 2021/111311 ?01/162020/061350
Figure imgf000048_0001
In step 4 of Example 1 (紅 5) -4- ((4- ((4-chloro-5-
（트라이플루오로메틸）피 리미딘- 2 -일）아미노）- 3 -메톡시페닐）아미노）아다만탄- 1 -올 대신에 （紅＜¾?5）-4-（4-（（4-（（4 -클로로- 5-（트라이플루오로메틸）피 리미딘- 2 - 일）아미노）- 3 -메톡시페닐）아미노）피페리딘- 1 -일）아다만탄- 1 -올을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 .
Figure imgf000048_0002
6 8.25 （ 111）， 8.15 （ 111）， 7.41 - 7.32 （111, 래）, 7.31 - 7.24 （111, 래）, 6.13 （（!, I = 2.3 ¾ , 내）, 5.97 （ 내）, 5.76 （ 내）, 3.78 （ 예）, 3.25 - 3.14 （111, 내）, 3.05 - 2.91 （111, 래）, 2.84 （（!, I = 4.8 예 ）, 2.39 - 2.31 （111, 래）, 2.21 （ 예）, 2.15 - 1.95 （111, 개）, 1.77 - 1.66 （111, 해）, 1.56 （111, 래）, 1.40 （111, 태）. (trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)adamantan-1-ol instead of (紅＜¾?5)-4-(4-((4) -((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)piperidin-1-yl)adamantan-1-ol The title compound was synthesized in the same manner as in Example 1.
Figure imgf000048_0002
6 8.25 ( 111), 8.15 ( 111), 7.41 - 7.32 (111, lower), 7.31 - 7.24 (111, lower), 6.13 ((!, I = 2.3 ¾ , within), 5.97 (within), 5.76 (within) ), 3.78 (example), 3.25 - 3.14 (111, inside), 3.05 - 2.91 (111, low), 2.84 ((!, I = 4.8 example), 2.39 - 2.31 (111, low), 2.21 (example), 2.15 - 1.95 (111, dog), 1.77 - 1.66 (111, year), 1.56 (111, young), 1.40 (111, young).
＜실시예
Figure imgf000048_0003
-하이드록시아다만탄- 2 -일）피페리딘- 4- 일）아미노）- 2 -메톡시페닐）아미노）- 5-（트라이즐루오로메틸）피리미딘- 4 -일）아미노）_ ᆻ 3 -다이메틸벤즈아마이드의 제조 （화합물 8）
Figure imgf000048_0004
<Example
Figure imgf000048_0003
-Hydroxyadamantan-2-yl)piperidin-4-yl)amino)-2 -methoxyphenyl)amino)-5-(trizluoromethyl)pyrimidin-4-yl)amino)_ ᆻ Preparation of 3-dimethylbenzamide (Compound 8)
Figure imgf000048_0004
[단계 1] （ 5）-4-（4-（（3-메톡시 -4-나이트로페닐）아미노）피페리딘-1_ 2021/111311 ?01/162020/061350 일）아다만탄- 1 -올의 제조
Figure imgf000049_0001
실시예 6의 단계 3 에서 아다만탄- 2 -온 대신에 5 -하이드록시아다만탄- 2- 온을 사용하여 실시예 6과 동일한 방법으로 표제 화합물을 합성하였다. [Step 1] (5)-4-(4-((3-methoxy-4-nitrophenyl)amino)piperidine-1_ 2021/111311 ?01/162020/061350 Sun) Production of Adamantane-1-ol
Figure imgf000049_0001
In step 3 of Example 6, the title compound was synthesized in the same manner as in Example 6 using 5-hydroxyadamantan-2-one instead of adamantan-2-one.
[단계 2] （ 5）-4-（4-（（4 -아미노- 3 -메톡시페닐）아미노）피페리딘- 1- 일）아다만탄- 1 -올의 제조
Figure imgf000049_0002
실시예 1 의 단계 2 에서 （ ^/^« ^-（（크-메톡시-간- 나이트로페닐）아미노）아다만탄- 1 -올 대신에 （ ）-4-（4-（（3 -메톡시- 4- 나이트로페닐）아미노）피페리딘- 1 -일）아다만탄- 1 -올을 사용하여 실시예 1과 동일한 방법으로 표제 화합물을 합성하였다. [Step 2] Preparation of (5)-4-(4-((4-amino-3-methoxyphenyl)amino)piperidin-1-yl)adamantan-1-ol
Figure imgf000049_0002
In Step 2 of Example 1 ( ^/^« ^-((K-methoxy-gan-nitrophenyl)amino)adamantan-1-ol instead of ( )-4-(4-((3 - The title compound was synthesized in the same manner as in Example 1 using methoxy-4-nitrophenyl)amino)piperidin-1-yl)adamantan-1-ol.
[단계 3] （ 5）-4-（4-（（4-（（4-클로로-5-（트라이플루오로메틸）피리미딘-2_ 일）아미노）- 3 -메톡시페닐）아미노）피페리딘- 1 -일）아다만탄- 1 -올의 제조
Figure imgf000049_0003
실시예 1 의 단계 3 에서 （ « - -（（간 -아미노- 3_ 메톡시페닐）아미노）아다만탄- 1 -올 대신에 （ 5）_4-（4-（（4 -아미노- 3- 2021/111311 ?01/162020/061350 메톡시페닐）아미노）피페리딘- 1 -일）아다만탄- 1 -올을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . [Step 3] (5)-4-(4-((4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)piperidin Diin- 1-yl) Preparation of adamantan- 1-ol
Figure imgf000049_0003
In step 3 of Example 1 ( «--((liver-amino-3_ methoxyphenyl)amino)adamantan-1-ol instead of ( 5 )_4-(4-((4-amino-3-3-) 2021/111311 -01/162020/061350 The title compound was synthesized in the same manner as in Example 1 using methoxyphenyl)amino)piperidin-1-yl)adamantan-1-ol.
[단계 4] 2-（（2-（（4-（（1-（（ 5）-5 -하이드록시아다만탄- 2 -일）피페리딘- 4- 일）아미노）- 2 -메톡시페닐）아미노）- 5-（트라이플루오로메틸）피 리미딘- 4 -일）아미노）_ ᄊ 3 -다이메틸벤즈아마이드의 제조
Figure imgf000050_0001
[Step 4] 2-((2-((4-((1-((5)-5-hydroxyadamantan-2-yl)piperidin-4-yl)amino)-2-methoxy Preparation of phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)_a 3-dimethylbenzamide
Figure imgf000050_0001
（트라이플루오로메틸）피 리미딘- 2 -일）아미노）- 3 -메톡시페닐）아미노）아다만탄- 1 -올 대신에 （ ）-4-（4-（（4-（（4 -클로로- 5-（트라이플루오로메틸）피 리미딘- 2 -일）아미노）_ 3 -메톡시페닐）아미노）피페리딘- 1 -일）아다만탄- 1 -올을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 .
Figure imgf000050_0002
6 8.25 （ 111）， 8.15 （ 111）， 7.41 - 7.32 （111, 래）, 7.31 - 7.24 （111, 래）, 6.13 （（!, I = 2.3 ¾ , 내）, 5.97 （ 내）, 5.76 （ 내）, 3.78 （ 예）, 3.25 - 3.14 （111, 내）, 3.05 - 2.91 （111, 래）, 2.84 （（!, I = 4.8 예 ）, 2.39 - 2.31 （111, 래）, 2.21 （ 예）, 2.15 - 1.95 （111, 개）, 1.77 - 1.66 （111, 해）, 1.56 （111, 래）, 1.40 （111, 태）. (Trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)adamantan-1-ol instead of ( )-4-(4-((4-((4-(4-) Example 1 using chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)_3-methoxyphenyl)amino)piperidin-1-yl)adamantan-1-ol The title compound was synthesized in the same manner as described above.
Figure imgf000050_0002
6 8.25 ( 111), 8.15 ( 111), 7.41 - 7.32 (111, lower), 7.31 - 7.24 (111, lower), 6.13 ((!, I = 2.3 ¾ , within), 5.97 (within), 5.76 (within) ), 3.78 (example), 3.25 - 3.14 (111, inside), 3.05 - 2.91 (111, low), 2.84 ((!, I = 4.8 example), 2.39 - 2.31 (111, low), 2.21 (example), 2.15 - 1.95 (111, dog), 1.77 - 1.66 (111, year), 1.56 (111, young), 1.40 (111, young).
＜실시예 9 ñ 2-（（2-（（4-（（1-（아다만탄- 2 -일）피페리딘- 4 -일）옥시）- 2- 메톡시페닐）아미노）- 5-（트라이쓸·루오로메틸）피리미딘- 4 -일）아미노）- 3- 다이메틸벤즈아마이드의 제조 （화합물 9） 2021/111311 ?01/162020/061350
Figure imgf000051_0001
<Example 9 - 2-((2-((4-((1-(adamantan-2-yl)piperidin-4-yl)oxy)-2-methoxyphenyl)amino)-5- Preparation of (trisul-luoromethyl)pyrimidin-4-yl)amino)-3-dimethylbenzamide (Compound 9) 2021/111311 ?01/162020/061350
Figure imgf000051_0001
[단계 1] 4-（（3 -메톡시- 4 -나이트로페닐）옥시）피페리딘- 1 -카복실산
Figure imgf000051_0002
부틸의 제조
Figure imgf000051_0003
실시예 1 의 단계 1 에서 <3 « 4 -아미노아다만탄- 1 -올 대신에 4 - 하이드록시피페리딘- 1 -카복실산 此/ -부틸을 사용하여 실시예 1과 동일한 방법으로 표제 화합물을 합성하였다. [Step 1] 4-((3-methoxy-4-nitrophenyl)oxy)piperidine-1-carboxylic acid
Figure imgf000051_0002
butyl production
Figure imgf000051_0003
In step 1 of Example 1, the title compound was prepared in the same manner as in Example 1, using 4-hydroxypiperidine-1-carboxylic acid 此/-butyl instead of <3 « 4-aminoadamantan-1-ol. synthesized.
[단계 2] 4-（3 -메톡시- 4 -나이트로페녹시）피페리딘의 제조
Figure imgf000051_0004
실시예 6의 단계 2에서 4-（（3 -메톡시- 4 -나이트로페닐）아미노）피페리딘- 1- 카복실산 此/ -부틸 대신에 4-（（3 -메톡시- 4 -나이트로페닐）옥시）피페리딘- 1- 카복실산 此/ -부틸을 사용하여 실시예 6 과 동일한 방법으로 표제 화합물을 합성하였다. [Step 2] Preparation of 4-(3-methoxy-4-nitrophenoxy)piperidine
Figure imgf000051_0004
In step 2 of Example 6, 4-((3-methoxy-4-nitrophenyl)amino)piperidine-1-carboxylic acid 此/-butyl instead of 4-((3-methoxy-4-nitro) The title compound was synthesized in the same manner as in Example 6 using phenyl)oxy)piperidine-1-carboxylic acid 此/-butyl.
[단계 3] 1-（아다만탄- 2 -일）- 4-（3 -메톡시- 4 -나이트로페녹시）피페리딘의 제조 2021/111311 ?01/162020/061350
Figure imgf000052_0001
실시 예 3 의 단계 2 에서 1-（3 -메톡시 - 4 -나이트로페닐）피페라진 대신에 4 - （3 -메톡시 - 4 -나이트로페녹시）피페리딘을 사용하여 실시 예 3 과 동일한 방법으로 표제 화합물을 합성하였다 . [Step 3] Preparation of 1-(adamantan-2-yl)- 4-(3-methoxy-4-nitrophenoxy)piperidine 2021/111311 ?01/162020/061350
Figure imgf000052_0001
Example 3 and Example 3 using 4-(3-methoxy-4-nitrophenoxy)piperidine instead of 1-(3-methoxy-4-nitrophenyl)piperazine in step 2 of Example 3 The title compound was synthesized in the same manner.
[단계 4] 4-（（1-（아다만탄- 2 -일）피페리딘- 4 -일）옥시）- 2 -메톡시아닐린의 제조
Figure imgf000052_0002
실시 예 1 의 단계 2 에서 （ ^/^« ^-（（크-메톡시 -간- 나이트로페닐 ）아미노）아다만탄- 1 -올 대신에 1-（아다만탄- 2 -일）- 4-（3 -메톡시 - 4- 나이트로페녹시 ）피페리딘을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . [Step 4] Preparation of 4-((1-(adamantan-2-yl)piperidin-4-yl)oxy)-2-methoxyaniline
Figure imgf000052_0002
In step 2 of Example 1, (^/^« ^-((k-methoxy-gan-nitrophenyl)amino)adamantan-1-ol 1-(adamantan-2-yl)- The title compound was synthesized in the same manner as in Example 1 using 4-(3-methoxy-4-nitrophenoxy)piperidine.
[단계 5] 聲（4-（（1-（아다만탄- 2 -일）피페리딘- 4 -일）옥시）- 2 -메톡시페닐）- 4- 클로로- 5-（트라이플루오로메틸）피 리미딘- 2 -아민의 제조
Figure imgf000052_0003
메톡시페닐 ）아미노）아다만탄- 1 -올 대신에 4-（（1-（아다만탄- 2 -일）피페리딘- 4- 일 ）옥시）- 2 -메톡시아닐린을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 2021/111311 ?01/162020/061350 합성하였다. [Step 5] 聲(4-((1-(adamantan-2-yl)piperidin-4-yl)oxy)-2-methoxyphenyl)-4-chloro-5-(trifluoromethyl ）Preparation of pyrimidine-2-amine
Figure imgf000052_0003
Methoxyphenyl )amino)adamantan-1-ol instead of 4-((1-(adamantan-2-yl)piperidin-4-yl)oxy)-2-methoxyaniline The title compound was prepared in the same manner as in Example 1. 2021/111311 ?01/162020/061350 Synthesized.
[단계 6] 2-（（2-（（4-（（1-（아다만탄- 2 -일）피페리딘- 4 -일）옥시）- 2- 메톡시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᄊ 3- 다이메틸벤즈아마이드의 제조
Figure imgf000053_0001
실시 예 1 의 단계 4 에서 （紅 ） -4-（（4-（（4 -클로로- 5-[Step 6] 2-((2-((4-((1-(adamantan-2-yl)piperidin-4-yl)oxy)-2-methoxyphenyl)amino)-5-( Preparation of trifluoromethyl)pyrimidin-4-yl)amino)- ᄊ 3-dimethylbenzamide
Figure imgf000053_0001
In step 4 of Example 1, (紅)-4-((4-((4-chloro-5-
（트라이플루오로메틸）피리미딘- 2 -일）아미노）- 3 -메톡시페닐）아미노）아다만탄- 1 -올 대신에 聲（4-（（1-（아다만탄- 2 -일）피페리딘- 4 -일）옥시）- 2 -메톡시페닐）- 4 -클로로- 5- （트라이플루오로메틸）피리미딘- 2 -아민을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다.
Figure imgf000053_0002
6 8.31 （加 111）， 8.27 （ 111）， 7.42 - 7.34(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)adamantan-1-ol instead of 聲(4-((1-(adamantan-2-yl)) The title compound was synthesized in the same manner as in Example 1 using piperidin-4-yl)oxy)-2-methoxyphenyl)-4-chloro-5-(trifluoromethyl)pyrimidin-2-amine. did.
Figure imgf000053_0002
6 8.31 (加 111), 8.27 ( 111), 7.42 - 7.34
（111, 래）, 7.28 （ᄂ I = 7.5 ¾ , 내）, 6.44 （（!, I = 1.9 ¾ , 내）, 6.08 （加 내）, 5.98 （ 내）, 4.16 （加 내）, 3.81 （ 예）, 2.92 - 2.81 （111, 태）, 2.20 （ 예）, 2.18 - 1.92 （111, ）, 1.92 - 1.75 （111, 해）, 1.75 - 1.57 （111, 仰）, 1.49 - 1.33 （111, 예）. (111, lower), 7.28 (ᄂ I = 7.5 ¾ , within), 6.44 ((!, I = 1.9 ¾ , within), 6.08 (within 加), 5.98 (within), 4.16 (within 加), 3.81 (eg ), 2.92 - 2.81 (111, tertiary), 2.20 (eg), 2.18 - 1.92 (111, ), 1.92 - 1.75 (111, year), 1.75 - 1.57 (111, 仰), 1.49 - 1.33 (111, eg) .
＜실시예 10 ñ 2-（（2-（（2 -메톡시- 4-（（4 -옥소아다만탄- 1- 일）옥시）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노'）- 113 - 다이메틸벤즈아마이드의 제조 （화합물 10） 2021/111311 1^(:1^2020/061350
Figure imgf000054_0001
<Example 10 - 2-((2-((2-methoxy-4-((4-oxoadamantan-1-yl)oxy)phenyl)amino)-5-(trifluoromethyl)pyrimidine - 4-yl) amino ' ) - 113 - Preparation of dimethylbenzamide (Compound 10) 2021/111311 1^(:1^2020/061350
Figure imgf000054_0001
[단계 1] 5-（3 -메톡시 - 4 -나이트로페녹시）아다만탄- 2 -온의 제조
Figure imgf000054_0002
실시 예 1 의 단계 1 에서 ^7? 4 -아미노아다만탄- 1 -올 대신에 5 - 하이드록시아다만탄- 2 -온을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . [Step 1] Preparation of 5-(3-methoxy-4-nitrophenoxy)adamantan-2-one
Figure imgf000054_0002
In step 1 of Example 1, ^7? The title compound was synthesized in the same manner as in Example 1 using 5-hydroxyadamantan-2-one instead of 4-aminoadamantan-1-ol.
[단계 2] 5-（4 -아미노- 3 -메톡시페녹시）아다만탄- 2 -온의 제조
Figure imgf000054_0003
_4_ ( (3 -메톡시 - 4- 나이트로페닐）아미노）아다만탄- 1 -올 대신에 5- (3 -메톡시 - 4- 나이트로페녹시）아다만탄- 2 -온을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . [Step 2] Preparation of 5-(4-amino-3-methoxyphenoxy)adamantan-2-one
Figure imgf000054_0003
_4_ Using 5-(3-methoxy-4-nitrophenoxy)adamantan-2-one instead of ((3-methoxy-4-nitrophenyl)amino)adamantan-1-ol The title compound was synthesized in the same manner as in Example 1.
[단계 3] 5-（4-（（4 -클로로- 5-（트라이플루오로메틸）피 리미딘- 2 -일）아미노）_[Step 3] 5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)_
3 -메톡시페녹시）아다만탄- 2 -온의 제조
Figure imgf000054_0004
2021/111311 ?01/162020/061350 실시 예 1 의 단계 3 에서 （ « - -（（간 -아미노- 3_ 메톡시페닐）아미노）아다만탄- 1 -올 대신에 5-（4 -아미노- 3 -메톡시페녹시）아다만탄- 2- 온을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다. Preparation of 3-methoxyphenoxy) adamantan-2-one
Figure imgf000054_0004
2021/111311 ?01/162020/061350 In step 3 of Example 1, 5-(4-amino-3 in place of ( «--((liver-amino-3_ methoxyphenyl)amino)adamantan-1-ol The title compound was synthesized in the same manner as in Example 1 using -methoxyphenoxy)adamantan-2-one.
[단계 6] 2-（（2-（（2 -메톡시- 4-（（4 -옥소아다만탄- 1 -일）옥시）페닐）아미노）_ 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᄊ 3 -다이메틸벤즈아마이드의 제조
Figure imgf000055_0001
[Step 6] 2-((2-((2-methoxy-4-((4-oxoadamantan-1-yl)oxy)phenyl)amino)_5-(trifluoromethyl)pyrimidine- Preparation of 4-yl)amino)- ᄊ 3-dimethylbenzamide
Figure imgf000055_0001
（트라이플루오로메틸）피리미딘- 2 -일）아미노）- 3 -메톡시페닐）아미노）아다만탄- 1 -올 대신에 聲（4-（（1-（아다만탄- 2 -일）피페리딘- 4 -일）옥시）- 2 -메톡시페닐）- 4 -클로로- 5- （트라이플루오로메틸）피리미딘- 2 -아민을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다.
Figure imgf000055_0002
6 8.46 （ 111）， 8.29 （ 111）， 7.42 - 7.35 （111, 래）, 7.28 （ᄂ / = 7.6 ¾ , 1¾， 6.45 （（!， / = 2.4 ¾， 111）， 6.17 （加 111）， 6.02 - 5.96 （111, 내）, 3.81 （ 예）, 2.88 （（1, I = 4.9 ¾ , 예）, 2.67 - 2.62 （111, 래）, 2.40 - 2.34 （111, 내）, 2.20 （ 예）, 2.19 - 2.01 （111, 仰）, 1.96 - 1.92 （111, 태） (trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)adamantan-1-ol instead of 聲(4-((1-(adamantan-2-yl)) The title compound was synthesized in the same manner as in Example 1 using piperidin-4-yl)oxy)-2-methoxyphenyl)-4-chloro-5-(trifluoromethyl)pyrimidin-2-amine. did.
Figure imgf000055_0002
6 8.46 ( 111), 8.29 ( 111), 7.42 - 7.35 (111, lower), 7.28 (ᄂ / = 7.6 ¾ , 1¾, 6.45 ((!, / = 2.4 ¾, 111), 6.17 (加 111), 6.02 - 5.96 (111, In), 3.81 (Ex), 2.88 ((1, I = 4.9 ¾ , Ex), 2.67 - 2.62 (111, Ra), 2.40 - 2.34 (111, In), 2.20 (Ex), 2.19 - 2.01 (111, 仰), 1.96 - 1.92 (111, tae)
＜실시예 11 ñ 2-（（2-（（4-（（4 -하이드록시아다만탄- 1 -일）옥시）- 2- 메록시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ; 3- 다이메틸벤즈아마이드의 제조 （화합물 11） 2021/111311 1^(:1^2020/061350
Figure imgf000056_0001
<Example 11 - 2-((2-((4-((4-hydroxyadamantan-1-yl)oxy)-2-meroxyphenyl)amino)-5-(trifluoromethyl)pyri midin-4-yl)amino)-; 3- Preparation of dimethylbenzamide (Compound 11) 2021/111311 1^(:1^2020/061350
Figure imgf000056_0001
［단계 1] 2-（（2-（（4-（（4 -하이드록시아다만탄- 1 -일）옥시）-2 - 메톡시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᄊ 3- 다이메틸벤즈아마이드의 제조
Figure imgf000056_0002
상기 실시예 10 에서 제조한 2-（（2-（（2-메톡시-4-（（4-옥소아다만탄-1_ 일）옥시）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᄊ3_ 다이메틸벤즈아마이드， 트라이아세톡시소듐보로하이드라이드， 테트라하이드로퓨란， 아세트산을 상온에서 15 시간 동안 교반하였다. 반응 용액에 얼음물을 부은 후 아세트산 에틸로 추출하고 무수 황산 마그네슘으로 건조 후 거르고， 여액을 농축한 후 컬럼 크로마토그래피로 정제하여 표제 화합물을 얻었다. [Step 1] 2-((2-((4-((4-hydroxyadamantan-1-yl)oxy)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidine - 4-yl) amino) - ᄊ Preparation of 3-dimethylbenzamide
Figure imgf000056_0002
2-((2-((2-methoxy-4-((4-oxoadamantan-1_yl)oxy)phenyl)amino)-5-(trifluoromethyl)pyri prepared in Example 10 Midin-4-yl)amino)- ᄊ3_ Dimethylbenzamide, triacetoxysodium borohydride, tetrahydrofuran, and acetic acid were stirred at room temperature for 15 hours. Ice water was poured into the reaction solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain the title compound.
¾ ■ (400 , 0-(16): 6 9.15 (¾, 페, 8.30 (¾, 페, 8.29 - 8.25¾ ■ (400 , 0-(1 6 ): 6 9.15 ( ¾ , pe, 8.30 ( ¾ , pe, 8.29 - 8.25)
(111, 내), 8.06 ( 내), 7.42 ((1, / = 7.4
Figure imgf000056_0004
내), 7.38 ((1, / = 7.2
Figure imgf000056_0003
(111, my), 8.06 (my), 7.42 ((1, / = 7.4)
Figure imgf000056_0004
within), 7.38 ((1, / = 7.2)
Figure imgf000056_0003
7.32 - 7.24 (111, 래), 6.51 ((1, /= 1.8
Figure imgf000056_0005
내), 6.21 (加 내), 4.66 ((1, / =7.32 - 7.24 (111, lower), 6.51 ((1, /= 1.8)
Figure imgf000056_0005
within), 6.21 (within 加), 4.66 ((1, / =
3.1 내), 3.70 ( 예), 3.69 - 3.66 (111, 내), 2.69 ((1, I = 4.6, 예), 2.103.1 within), 3.70 (eg), 3.69 - 3.66 (111, within), 2.69 ((1, I = 4.6, eg), 2.10
( 예), 2.05 - 1.91 (111, 해), 1.84 - 1.71 (111, 仰), 1.26 - 1.23 (111, ¾) 2021/111311 ?01/162020/061350(Example), 2.05 - 1.91 (111, year), 1.84 - 1.71 (111, 仰), 1.26 - 1.23 (111, ¾) 2021/111311 ?01/162020/061350
＜실시예 12 ñ 2-（（2-（（2 -메톡시- 4-（（4 -몰포리노아다만탄- 1- 일）옥시）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）-成 3 - 다이메틸벤즈아마이드의 제조 （화합물 12）
Figure imgf000057_0001
<Example 12 - 2-((2-((2-methoxy-4-((4-morpholinoadamantan-1-yl)oxy)phenyl)amino)-5-(trifluoromethyl)pyri Preparation of midin-4-yl)amino)-成3-dimethylbenzamide (Compound 12)
Figure imgf000057_0001
[단계 1] 2-（（2-（（2-메톡시-4-（（4-몰포리노아다만탄-1_ 일）옥시）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᄊ3_ 다이메틸벤즈아마이드의 제조
Figure imgf000057_0002
상기 실시예 10 에서 제조한 2-（（2-（（2-메톡시-4-（（4-옥소아다만탄-1_ 일）옥시）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᄊ3_ 다이메틸벤즈아마이드， 몰포린， 트라이아세톡시소듐보로하이드라이드， 테트라하이드로퓨란， 아세트산을 상온에서 15 시간 동안 교반하였다. 반응 용액에 얼음물을 부은 후 아세트산 에틸로 추출하고 무수 황산 마그네슘으로 건조 후 거르고， 여액을 농축한 후 컬럼 크로마토그래피로 정제하여 표제 화합물을 얻었다. [Step 1] 2-((2-((2-methoxy-4-((4-morpholinoadamantan-1_yl)oxy)phenyl)amino)-5-(trifluoromethyl)pyrimidine- 4-yl) amino)- ᄊ3_ dimethylbenzamide production
Figure imgf000057_0002
2-((2-((2-methoxy-4-((4-oxoadamantan-1_yl)oxy)phenyl)amino)-5-(trifluoromethyl)pyri prepared in Example 10 Midin-4-yl)amino)- ᄊ3_ Dimethylbenzamide, morpholine, triacetoxysodium borohydride, tetrahydrofuran, and acetic acid were stirred at room temperature for 15 hours. Ice water was poured into the reaction solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain the title compound.
¾ » （400 ， 0-（16）: 6 9.07 ， 페， 8.24 ， 페， 8.23 - 8.17 （111, 페 , 8.01
Figure imgf000057_0003
페 , 7.38 - 7.30 （111, 2¾， 7.26 - 7.19 （111, ¾） , 6.46
Figure imgf000057_0004
페 , 6.15 （加 ， 페 , 3.65 （ 예）, 3.54 （加 ， , 3.27 （ 예）, 2.63 （（1, / = 4.5 2021/111311 ?01/162020/061350¾ » （400 ， 0-（1 6 ）: 6 9.07 ， Pe， 8.24 ， Pe， 8.23 - 8.17 （111, Pe , 8.01
Figure imgf000057_0003
Pe, 7.38 - 7.30 (111, 2¾, 7.26 - 7.19 (111, ¾) , 6.46
Figure imgf000057_0004
Pe, 6.15 (加, Pe, 3.65 (Ex), 3.54 (加, , 3.27 (Ex)), 2.63 ((1, / = 4.5) 2021/111311 ?01/162020/061350
¾ , 예）, 2.45 （加 태）, 2.34 - 2.15 （111, ¾）, 2.04
Figure imgf000058_0001
예）, 1.92 - 1.64 （111, 개）, 1.21 - 1.11 （111, ¾） ¾ , eg), 2.45 （加 Tae）, 2.34 - 2.15 （111, ¾）, 2.04
Figure imgf000058_0001
ex), 1.92 - 1.64 (111, pcs), 1.21 - 1.11 (111, ¾)
<실시예 13> 2-（（2-（（2 -메특시- 4-（（4-（4 -메틸피페라진-!-일）아다만탄- 1- 일）옥시）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- 3 - 다이메틸벤즈아마이드의 제조 （화합물 13）
Figure imgf000058_0002
<Example 13> 2-((2-((2-Metoxy-4-((4-(4-methylpiperazin-!-yl)adamantan-1-yl)oxy)phenyl)amino)- Preparation of 5-(trifluoromethyl)pyrimidin-4-yl)amino)-3-dimethylbenzamide (Compound 13)
Figure imgf000058_0002
[단계 1] 2-（（2-（（2-메톡시-4-（（4-（4-메틸피페라진-1-일）아다만탄-1_ 일）옥시）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᄊ3_ 다이메틸벤즈아마이드의 제조
Figure imgf000058_0003
실시 예 12 의 단계 1 에서 몰포린 대신에 4 -메틸피페라진을 사용하여 실시 예 12 와 동일한 방법으로 표제 화합물을 합성하였다.
Figure imgf000058_0004
6 8.50 （ ^）, 8.26（ ^）, 7.42 - 7.36 （111, 래）, 7.28 （ᄂ I = 7.5 ¾ , 내）, 6.45 （（1, I = 2.3 ¾ , 내）, 6.21 - 6.08 （111, 래）, 3.80 （ 예）, 3.50 - 3.40 （111, 래）, 3.15 - 2.65 （111, 12¾， 2.28 - 2.22 （111, 내）, 2.20 （ 예）, 2.16 - 1.64 （111, 11 ， 1.32 - 1.22 （111, ¾） 2021/111311 ?01/162020/061350 [Step 1] 2-((2-((2-methoxy-4-((4-(4-methylpiperazin-1-yl)adamantan-1_yl)oxy)phenyl)amino)-5- Preparation of (trifluoromethyl)pyrimidin-4-yl)amino)- ᄊ3_ dimethylbenzamide
Figure imgf000058_0003
The title compound was synthesized in the same manner as in Example 12 using 4-methylpiperazine instead of morpholine in Step 1 of Example 12.
Figure imgf000058_0004
6 8.50 ( ^), 8.26 ( ^), 7.42 - 7.36 (111, lower), 7.28 (ᄂ I = 7.5 ¾ , in), 6.45 ((1, I = 2.3 ¾ , in), 6.21 - 6.08 (111, Rae), 3.80 (Example), 3.50 - 3.40 (111, Rae), 3.15 - 2.65 (111, 12¾, 2.28 - 2.22 (111, Inner), 2.20 (Example), 2.16 - 1.64 (111, 11 , 1.32 - 1.22) (111, ¾) 2021/111311 ?01/162020/061350
＜실시예 14＞ 2-（（2_（（4_（（（ /¾/35!）_4-（（5）-3 -아세트아마이도피롤리딘_1_ 일）아다만탄-；！-일）옥시）- 2 -메톡시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘 -4 - 일）아미노）- ·， 3 -다이메틸벤즈아마이드의 제조 （화합물 14）
Figure imgf000059_0001
<Example 14> 2-((2_((4_((( /¾/35!) _ 4-((5)-3 -acetamidopyrrolidine_1_ days) adamantane-;!- days)) Preparation of oxy)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)- · , 3-dimethylbenzamide (Compound 14)
Figure imgf000059_0001
[단계 1] 2-（（2-（（4-（（（ ）-4-（（ 5）-3 -아세트아마이도피롤리딘- 1- 일）아다만탄- 1 -일）옥시）- 2 -메톡시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘_ 4 -일）아미노） -ᄊ 3 -다이메틸벤즈아마이드의 제조
Figure imgf000059_0002
실시예 12 의 단계 1 에서 몰포린 대신에 （5） -聲（피롤리딘- 3- 일）아세트아마이드를 사용하여 실시예 12 와 동일한 방법으로 표제 화합물을 합성하였다. [Step 1] 2-((2-((4-((( )-4-((5)-3 -acetamidopyrrolidin-1-yl)adamantan-1-yl)oxy)-2 -Methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin_ 4-yl)amino)-ᄊ 3-dimethylbenzamide
Figure imgf000059_0002
The title compound was synthesized in the same manner as in Example 12, using (5)-聲(pyrrolidin-3-yl)acetamide in step 1 of Example 12 instead of morpholine.
¾ » （400 ， 0-（16）: 6 9.14 ， 페， 8.29 ， 페， 8.28 - 8.24 （111, 내）, 8.04 （ 내）, 7.95 （（!, I = 6.6 ¾ , 내）, 7.42 （（!, I = 7.5 ¾ , 내）, 7.38 （（1, / = 7.1 ¾ , 내）, 7.32 - 7.24 （111, 래）, 6.50 （（1, I = 1.7 ¾ , 내）, 6.20 （加 내）, 5.75 （ 내）, 4.19 - 4.08 （111, 내）, 3.70 （ 예）, 2.77 - 2.62 （111, 태）, 2.55 （111, 내）, 2.43 （111, 내）, 2.24 （111, 내）, 2.21 - 1.90 （111, 1아1）, 1.78 （ 2021/111311 ?01/162020/061350 예）, 1.71 （111, 래）, 1.56 - 1.43 （111, 개） ¾ » （400 ， 0-（1 6 ）: 6 9.14 , pe, 8.29 , pe, 8.28 - 8.24 (111, within), 8.04 ( within), 7.95 ((!, I = 6.6 ¾ , within), 7.42 ( (!, I = 7.5 ¾ , within), 7.38 ((1, / = 7.1 ¾ , within), 7.32 - 7.24 (111, below), 6.50 ((1, I = 1.7 ¾ , within), 6.20 （within 加), 5.75 (inside), 4.19 - 4.08 (111, within), 3.70 (ex), 2.77 - 2.62 (111, within), 2.55 (111, within), 2.43 (111, within), 2.24 (111, within) , 2.21 - 1.90 (111, 1a1), 1.78 ( 2021/111311 ?01/162020/061350 Yes), 1.71 (111, lower), 1.56 - 1.43 (111, number)
<실시예 15> 2-（（2-（（4-（（（ 5）-4-（（5）-3-아세트아마이도피롤리딘-1- 일）아다만탄- 1 -일）옥시）- 2 -메톡시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4- 일）아미노）- ·， 3 -다이메틸벤즈아마이드의 제조 （화합물 15）
Figure imgf000060_0001
<Example 15> 2-((2-((4-(((5)-4-((5)-3-acetamidopyrrolidin-1-yl)adamantan-1-yl)oxy) - 2-Methoxyphenyl) amino) - 5- (trifluoromethyl) pyrimidin-4-yl) amino) - · , 3-dimethylbenzamide preparation (Compound 15)
Figure imgf000060_0001
[단계 1] 2-（（2-（（4-（（（ 5）-4-（（ 5）-3 -아세트아마이도피롤리딘- 1- 일）아다만탄- 1 -일）옥시）- 2 -메톡시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘_ 4 -일）아미노） -ᄊ 3 -다이메틸벤즈아마이드의 제조
Figure imgf000060_0002
실시 예 12 의 단계 1 에서 몰포린 대신에 （5） -聲（피롤리딘- 3- 일）아세트아마이드를 사용하여 실시 예 12 와 동일한 방법으로 표제 화합물을 합성하였다. [Step 1] 2-((2-((4-(((5)-4-((5)-3-acetamidopyrrolidin-1-yl)adamantan-1-yl)oxy)- Preparation of 2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin_4-yl)amino)-ᄊ 3-dimethylbenzamide
Figure imgf000060_0002
The title compound was synthesized in the same manner as in Example 12 using (5)-聲(pyrrolidin-3-yl)acetamide in step 1 of Example 12 instead of morpholine.
¾ » （400 ， 0-（16）: 6 9.13 （ 페， 8.30 （ 페， 8.29 - 8.23¾ » （400 ， 0-（1 6 ）: 6 9.13 （ Pe, 8.30 （ Pe, 8.29 - 8.23
（111, 내）, 8.05 （ 내）, 7.93 （（1, / = 4.9
Figure imgf000060_0003
내）, 7.41 （（1, / = 7.5 ¾ , 페 ,(111, within), 8.05 (within), 7.93 ((1, / = 4.9)
Figure imgf000060_0003
within), 7.41 (（1, / = 7.5 ¾ , pe ,
7.38 （（1, / = 7.1 ¾ , 내）, 7.32 - 7.24 （111, 래）, 6.52 （（1, I = 1.2
Figure imgf000060_0004
내）, 6.21 （加 ， 내）, 5.75 （ 내）, 4.19 - 4.08 （111, 내）, 3.70 （ 예）, 2.81 - 2.54 （111, 2021/111311 ?01/162020/061350 태）， 2.50 （111, 내）, 2.44 - 2.20 （111, 래）, 2.20 - 1.87 （111, ）, 1.87 - 1.64 （111, 개）, 1.64 - 1.38 （111, 래）, 1.38 - 1.04 （111, 해）. 7.38 ((1, / = 7.1 ¾ , in), 7.32 - 7.24 (111, lower), 6.52 ((1, I = 1.2)
Figure imgf000060_0004
Inner), 6.21 (加, Inner), 5.75 (Inner), 4.19 - 4.08 (111, Inner), 3.70 (Example), 2.81 - 2.54 (111, 2021/111311 ?01/162020/061350 Tae), 2.50 (111, inner), 2.44 - 2.20 (111, lower), 2.20 - 1.87 (111, ), 1.87 - 1.64 (111, number), 1.64 - 1.38 (111 , Ra), 1.38 - 1.04 (111, year).
<실시예 16> 4-（3 -메톡시- 4-（（4-（（2 -메틸- 6-（메틸카바모일）페닐）아미노）_ 5-（트라이플루오로메틸）피리미딘- 2 -일）아미노）페녹시）아다만테인- 1 -카복실산 메틸의 제조 （화합물 16）
Figure imgf000061_0001
<Example 16> 4-(3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)_5-(trifluoromethyl)pyrimidine-2- Preparation of yl)amino)phenoxy)adamantane-1-methyl carboxylate (Compound 16)
Figure imgf000061_0001
[단계 1] 4-（3 -메톡시- 4 -나이트로페녹시）아다만테인- 1 -카복실산 메틸의 제조
Figure imgf000061_0002
실시 예 1 의 단계 1 에서 <3 « 4 -아미노아다만탄- 1 -올 대신에 4 - 하이드록시아다만테인- 1 -카복실산 메틸을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다. [Step 1] Preparation of 4-(3-methoxy-4-nitrophenoxy)adamantane-1 -methyl carboxylate
Figure imgf000061_0002
In step 1 of Example 1, the title compound was synthesized in the same manner as in Example 1, using methyl 4-hydroxyadamantane-1-carboxylate instead of <3 « 4-aminoadamantan-1-ol.
[단계 2] 4-（4 -아미노- 3 -메톡시페녹시）아다만테인- 1 -카복실산 메틸의 제조
Figure imgf000061_0003
실시 예 1 의 단계 2 에서 （ /^^ ^-（ -메톡시-간- 2021/111311 ?01/162020/061350 나이트로 페닐）아미노）아다만탄- 1 -올 대신에 4- (3 -메톡시 - 4 - 나이트로 페녹시）아다만테인- 1 -카복실산 메틸을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . [Step 2] Preparation of 4-(4-amino-3-methoxyphenoxy)adamantane-1-carboxylate methyl
Figure imgf000061_0003
In step 2 of Example 1 ( /^^ ^-( -methoxy-between- 2021/111311 ?01/162020/061350 Using 4-(3-methoxy-4-nitrophenoxy)adamantane-1-carboxylate methyl instead of nitrophenyl)amino)adamantan-1-ol The title compound was synthesized in the same manner as in Example 1.
[단계 3] 4-（4-（（4 -클로로- 5-（트라이플루오로메틸）피 리미딘- 2 -일）아미노）_ 3 -메톡시페녹시）아다만테인- 1 -카복실산 메틸의 제조
Figure imgf000062_0001
실시 예 1 의 단계 3 에서 （ /"/ /^- （（갇-아미노- 메톡시페닐）아미노）아다만탄- 1 -올 대신에 4-（4 -아미노- 3 -메톡시페녹시）아다만테인_ 1 -카복실산 메틸을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . [Step 3] 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)_3-methoxyphenoxy)adamantane- 1-methyl carboxylate Produce
Figure imgf000062_0001
In step 3 of Example 1, ( /"/ /^- ((trapped-amino- methoxyphenyl) amino) 4-(4-amino-3- methoxyphenoxy) instead of adamantan-1-ol The title compound was synthesized in the same manner as in Example 1 using damantane_ 1-methyl carboxylate.
[단계 4] 4-（3 -메톡시 - 4-（（4-（（2 -메틸- 6-（메틸카바모일）페닐）아미노）- 5-[Step 4] 4-(3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)-5-
（트라이플루오로메틸）피 리미딘- 2 -일）아미노）페녹시）아다만테인- 1 -카복실산 메틸의 제조
Figure imgf000062_0002
실시 예 1 의 단계 4 에서 （紅 ） -4-（（4-（（4 -클로로- 5-Preparation of (trifluoromethyl)pyrimidin-2-yl)amino)phenoxy)adamantane-1-methyl carboxylate
Figure imgf000062_0002
In step 4 of Example 1, (紅)-4-((4-((4-chloro-5-
（트라이플루오로메틸）피 리미딘- 2 -일）아미노）- 3 -메톡시페닐）아미노）아다만탄- 1 -올 대신에 4_（4_（（4 -클로로- 5_（트라이플루오로메틸）피 리미딘- 2 -일）아미노）- 3- 메톡시페녹시）아다만테인- 1 -카복실산 메틸을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . 2021/111311 ?01/162020/061350 (Trifluoromethyl) the limiter Dean-2-yl) amino) - 3-methoxyphenyl) amino) adamantan-1-ol instead of 4 _ (4 _ ((4-chloro-5 _ (trifluoromethyl The title compound was synthesized in the same manner as in Example 1 using romethyl)pyrimidin-2-yl)amino)-3-methoxyphenoxy)adamantane-1-carboxylate methyl. 2021/111311 ?01/162020/061350
¾ » （400 ， 0[13）: 6 8.40 ， 페， 8.26 ， 페， 7.51 ， ¾）， 7.30 （111, 예）, 6.44
Figure imgf000063_0001
페 , 6.11 （111, 2¾， 4.25 （111, 페 , 3.79
Figure imgf000063_0002
예）, 3.66 （111, 예 ）, 2.82 （（1, I = 4.9 ¾ , 예）, 2.32 - 2.10 （111, 仰）, 2.06 - 1.80 （111, 개）, 1.77 - 1.65 （111, 래）, 1.48
Figure imgf000063_0003
¾ » (400 , 0[1 3 ): 6 8.40 , pe, 8.26 , pe, 7.51 , ¾), 7.30 (111, ex), 6.44
Figure imgf000063_0001
Pe , 6.11 （111, 2¾， 4.25 （111, Pe , 3.79
Figure imgf000063_0002
ex), 3.66 (111, ex), 2.82 ((1, I = 4.9 ¾ , ex), 2.32 - 2.10 (111, 仰), 2.06 - 1.80 (111, ea), 1.77 - 1.65 (111, rae), 1.48
Figure imgf000063_0003
<실시예 17> 4-（3 -메톡시- 4-（（4-（（2 -메틸- 6-（메틸카바모일）페닐）아미노）_ 5-（트라이플루오로메틸）피리미딘- 2 -일）아미노）페녹시）아다만테인- 1 -카복실산의 제조 （화합물 17）
Figure imgf000063_0004
<Example 17> 4-(3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)_5-(trifluoromethyl)pyrimidine-2- Preparation of work) amino) phenoxy) adamantane-1-carboxylic acid (compound 17)
Figure imgf000063_0004
[단계 1] 4-（3 -메톡시- 4-（（4-（（2 -메틸- 6-（메틸카바모일）페닐）아미노）- 5 -[Step 1] 4-(3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)-5-
（트라이플루오로메틸）피리미딘- 2 -일）아미노）페녹시）아다만테인- 1 -카복실산의 제조
Figure imgf000063_0005
상기 실시 예 16 에서 제조한 4-（3 -메톡시- 4-（（4-（（2 -메틸- 6-Preparation of (trifluoromethyl)pyrimidin-2-yl)amino)phenoxy)adamantane-1-carboxylic acid
Figure imgf000063_0005
4-(3-methoxy-4-((4-((2-methyl-6-) prepared in Example 16 above
（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）페녹시）아다만테인- 1 -카복실산 메틸에 염산 수용액을 가한 후 5 시간 동안 환류 교반하였다. 반응 완료 후 반응 용액에 증류수를 가하고 다이클로로메 테인으로 추출하였다. 무수 황산 마그네슘으로 건조 후 여과하고 2021/111311 ?01/162020/061350 여 액을 농축한 후 컬럼 크로마토그래피로 정제하여 표제 화합물을 얻었다 .
Figure imgf000064_0001
6 8.16 （ 111）， 7.43 - 7.28 （111, 태）, 6.43 （111, 내）, 6.02 （ 래）, 4.28 （111, 내）, 3.82 （111, 예）, 2.90 （（!, I = 4.2 ¾ , 예）, 2.61 （111, 페 , 2.27 （111, 예）, 2.16 （ 예）, 2.11 - 1.84 （111, 5¾， 1.79 - 1.70 （111, 예）,(Methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenoxy)adamantane-1-carboxylic acid Aqueous hydrochloric acid solution was added to methyl carboxylate, and the mixture was stirred under reflux for 5 hours. . After completion of the reaction, distilled water was added to the reaction solution, followed by extraction with dichloromethane. After drying over anhydrous magnesium sulfate, filtered 2021/111311 -01/162020/061350 The filtrate was concentrated and purified by column chromatography to obtain the title compound.
Figure imgf000064_0001
6 8.16 ( 111), 7.43 - 7.28 (111, Tae), 6.43 (111, In), 6.02 (L), 4.28 (111, In), 3.82 (111, Ex), 2.90 ((!, I = 4.2 ¾ , eg), 2.61 (111, pe, 2.27 (111, eg), 2.16 (eg), 2.11 - 1.84 (111, 5¾, 1.79 - 1.70 (111, eg),
1.52 （111, 1 1.52 (111, 1
<실시예 18> 4-（3 -메톡시- 4-（（4-（（2 -메틸- 6-（메틸카바모일）페닐）아미노）_ 5-（트라이플루오로메틸）피리미딘- 2 -일）아미노）페녹시） -/ V·메틸아다만테인-1_ 카복사마이드의 제조（화합물 18）
Figure imgf000064_0002
<Example 18> 4-(3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)_5-(trifluoromethyl)pyrimidine-2- yl) amino) phenoxy) - / V methyladamantane-1_ carboxamide preparation (compound 18)
Figure imgf000064_0002
[단계 1] 4-（3 -메톡시 - 4-（（4-（（2 -메틸- 6-（메틸카바모일）페닐）아미노）- 5-[Step 1] 4-(3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)-5-
（트라이플루오로메틸）피 리미딘- 2 -일）아미노）페녹시）- 메틸아다만테인- 1- 카복사마이드의 제조
Figure imgf000064_0003
상기 실시 예 16 에서 제조한 4-（3 -메톡시 - 4-（（4-（（2 -메틸- 6-Preparation of (trifluoromethyl)pyrimidin-2-yl)amino)phenoxy)-methyladamantane-1-carboxamide
Figure imgf000064_0003
4-(3-methoxy-4-((4-((2-methyl-6-) prepared in Example 16
（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피 리미딘- 2- 일）아미노）페녹시）아다만테인- 1 -카복실산， 메틸아민 염산염， 1 - 2021/111311 ?01/162020/061350(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenoxy)adamantane-1-carboxylic acid, methylamine hydrochloride, 1- 2021/111311 ?01/162020/061350
[비스（다이메틸아미노）메틸렌] -1 1， 2， 3 -트라이아졸로 [4， 5 -別피리디늄 3 -옥사이드 핵사플루오로포스페이트를 ᄊ 다이메틸폼아마이드에 녹인 후 트라이에틸아민을 가하여 5 시간 동안 상온에서 교반하였다. 반응 완료 후 반응 용액에 증류수를 가하고 아세트산 에틸로 추출하였다. 무수 황산 마그네슘으로 건조 후 여과하고 여 액을 농축한 후 컬럼 크로마토그래피로 정제하여 표제 화합물을 얻었다. [Bis (dimethylamino) methylene] -1 1, 2, 3-triazolo [4, 5-別pyridinium 3-oxide hexafluorophosphate was dissolved in ᄊ dimethylformamide, and then triethylamine was added to 5 It was stirred at room temperature for hours. After completion of the reaction, distilled water was added to the reaction solution, followed by extraction with ethyl acetate. It was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain the title compound.
¾ » （400 ， 0[13）: 6 8.33 ， 페， 8.28 ， 페， 7.52 ， ¾），¾ » (400 , 0[1 3 ): 6 8.33 , pe, 8.28 , pe, 7.52 , ¾),
7.38 （111, 래）, 7.33 - 7.18 （111, 내）, 6.46 （ 내）, 6.03 （111, 래）, 5.63 （ 내）,7.38 (111, old), 7.33 - 7.18 (111, my), 6.46 (my), 6.03 (111, my), 5.63 (my),
4.28 （111, 내）, 3.82 （ 예）, 2.91 - 2.72 （111, 仰）, 2.30 - 2.12 （111, 仰）, 2.09 -4.28 (111, Inner), 3.82 (Example), 2.91 - 2.72 (111, 仰), 2.30 - 2.12 (111, 仰), 2.09 -
1.82 （111, 仰）, 1.79 - 1.63 （111, 래）, 1.53 - 1.43 （111, ¾） 1.82 (111, 仰), 1.79 - 1.63 (111, lower), 1.53 - 1.43 (111, ¾)
<실시예 19> 2-（（2-（（2 -메톡시- 4-（（5-（몰포린- 4 -카보닐）아다만탄- 2- 일）옥시）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᆻ 3 - 다이메틸벤즈아마이드의 제조 （화합물 19）
Figure imgf000065_0001
<Example 19> 2-((2-((2-methoxy-4-((5-(morpholine-4-carbonyl)adamantan-2-yl)oxy)phenyl)amino)-5- Preparation of (trifluoromethyl)pyrimidin-4-yl)amino)-ᆻ3-dimethylbenzamide (Compound 19)
Figure imgf000065_0001
[단계 1] 2-（（2-（（2 -메톡시- 4-（（5-（몰포린- 4 -카보닐）아다만탄- 2- 일）옥시）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᄊ3_ 다이메틸벤즈아마이드의 제조 2021/111311 ?01/162020/061350
Figure imgf000066_0001
실시 예 18 의 단계 1 에서 메틸아민 염산염 대신에 몰포린을 사용하여 실시 예[Step 1] 2-((2-((2-methoxy-4-((5-(morpholine-4-carbonyl)adamantan-2-yl)oxy)phenyl)amino)-5-( Preparation of trifluoromethyl)pyrimidin-4-yl)amino)- ᄊ3_ dimethylbenzamide 2021/111311 ?01/162020/061350
Figure imgf000066_0001
Example 18 using morpholine instead of methylamine hydrochloride in step 1 of Example 18
18 과 동일한 방법으로 표제 화합물을 합성하였다.
Figure imgf000066_0002
0[13）: 6 8.36 （111, ^）, 8.28 （ ^）, 7.52 （ 2¾，The title compound was synthesized in the same manner as in 18.
Figure imgf000066_0002
0[1 3 ): 6 8.36 (111, ^), 8.28 ( ^), 7.52 ( 2¾,
7.38 （111, 래）, 7.34 - 7.26 （111, 내）, 6.43 （111, 내）, 6.01 （111, 래）, 4.28 （ 내）, 3.81 （111, 예）, 3.78 - 3.65 （111, 仰）, 2.87 （111, 예）, 2.41 （111, 내）, 2.31 - 2.13 （111, 仰）, 2.12 - 1.95 （111, 예）, 1.92 - 1.81 （111, 내）, 1.80 - 1.67 （111, 래）, 1.65 - 1.45 （111, 2 7.38 (111, lower), 7.34 - 7.26 (111, inner), 6.43 (111, inner), 6.01 (111, lower), 4.28 (inner), 3.81 (111, yes), 3.78 - 3.65 (111, 仰) , 2.87 (111, yes), 2.41 (111, inner), 2.31 - 2.13 (111, 仰), 2.12 - 1.95 (111, yes), 1.92 - 1.81 (111, inner), 1.80 - 1.67 (111, lower) , 1.65 - 1.45 （111, 2
<실시예 20> 2-（（2-（（2 -메톡시- 4-（（5-（4 -메틸피페라진- 1 -카보닐）아다만탄_ 2 -일）옥시）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）-成 3 - 다이메틸벤즈아마이드의 제조 （화합물 20）
Figure imgf000066_0003
<Example 20> 2-((2-((2-methoxy-4-((5-(4-methylpiperazine-1-carbonyl)adamantan_2-yl)oxy)phenyl)amino) - Preparation of 5-(trifluoromethyl)pyrimidin-4-yl)amino)-produced 3-dimethylbenzamide (Compound 20)
Figure imgf000066_0003
[단계 1] 2-（（2-（（2 -메톡시- 4-（（5-（4 -메틸피페라진- 1 -카보닐）아다만탄- 2- 일）옥시）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᄊ3_ 다이메틸벤즈아마이드의 제조 2021/111311 ?01/162020/061350
Figure imgf000067_0001
실시 예 18 의 단계 1 에서 메틸아민 염산염 대신에 1 -메틸피페라진을 사용하여 실시 예 18 과 동일한 방법으로 표제 화합물을 합성하였다 . [Step 1] 2-((2-((2-methoxy-4-((5-(4-methylpiperazine-1-carbonyl)adamantan-2-yl)oxy)phenyl)amino)- Preparation of 5-(trifluoromethyl)pyrimidin-4-yl)amino)- ᄊ3_ dimethylbenzamide 2021/111311 ?01/162020/061350
Figure imgf000067_0001
The title compound was synthesized in the same manner as in Example 18 using 1-methylpiperazine in Step 1 of Example 18 instead of methylamine hydrochloride.
¾ » （400 ， 0[13）: 6 8.35 ， 페， 8.27 ， 페， 7.51 ， ¾）， 7.38 （111, 2¾， 7.32 - 7.26 （111, 페 , 6.50 - 6.38 （111, 페 , 6.02
Figure imgf000067_0002
2¾， 4.28 （111, 내）, 3.81 （111, 예）, 3.74 （111, 태）, 2.86 （（!, I = 4.7
Figure imgf000067_0003
예）, 2.41 （ 해）, 2.31¾ » （400 ， 0[1 3 ]: 6 8.35 ， pe， 8.27 , pe， 7.51 ， ¾), 7.38 （111, 2¾, 7.32 - 7.26 （111, pe , 6.50 - 6.38 （111, pe , 6.02
Figure imgf000067_0002
2¾, 4.28 (111, within), 3.81 (111, yes), 3.74 (111, Tae), 2.86 ((!, I = 4.7)
Figure imgf000067_0003
ex), 2.41 (year), 2.31
（ 예）, 2.29 - 2.12 （111, 仰）, 2.01 （111, 태）, 1.87 （111, 래）, 1.71 （111, 래）, 1.51(Example), 2.29 - 2.12 (111, 仰), 2.01 (111, tae), 1.87 (111, rae), 1.71 (111, rae), 1.51
（111， 페 (111, P
<실시예 21> 2-（（2-（（2 -메톡시- 4-（（5-（（5）-3 -아세트아마이도피롤리딘- 1- 카보닐）아다만탄- 2 -일）옥시）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4- 일）아미노）- ; 3 -다이메틸벤즈아마이드의 제조 （화합물 21）
Figure imgf000067_0004
<Example 21> 2-((2-((2-methoxy-4-((5-((5)-3-acetamidopyrrolidine-1-carbonyl)adamantan-2-yl)) oxy)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)- ; Preparation of 3-dimethylbenzamide (Compound 21)
Figure imgf000067_0004
[단계 1] 2-（（2-（（2 -메톡시 - 4-（（5-（（5）-3 -아세트아마이도피롤리딘- 1- 카보닐）아다만탄- 2 -일）옥시）페닐）아미노）- 5-（트라이플루오로메틸）피 리미딘- 4- 일）아미노）- ᄊ 3 -다이메틸벤즈아마이드의 제조 2021/111311 ?01/162020/061350
Figure imgf000068_0001
실시 예 18 의 단계 1 에서 메틸아민 염산염 대신에 （5） -聲（피롤리딘- 3- 일）아세트아마이드를 사용하여 실시 예 18 과 동일한 방법으로 표제 화합물을 합성하였다.
Figure imgf000068_0002
0）이3）: 5 8.37 （111, 111）, 8.27 （ 111）, 7.50 （ ¾）,[Step 1] 2-((2-((2-methoxy-4-((5-((5)-3-acetamidopyrrolidine-1-carbonyl)adamantan-2-yl)oxy )Phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-a 3-dimethylbenzamide 2021/111311 ?01/162020/061350
Figure imgf000068_0001
The title compound was synthesized in the same manner as in Example 18, using (5)-聲(pyrrolidin-3-yl)acetamide in step 1 of Example 18 instead of methylamine hydrochloride.
Figure imgf000068_0002
0) 2 3 ): 5 8.37 (111, 111), 8.27 ( 111), 7.50 ( ¾),
7.43 - 7.34 （111, 래）, 7.29 （111, 내）, 6.46 （111, 내）, 6.10 （111, 래）, 5.58 （111, 내）,7.43 - 7.34 (111, my), 7.29 (111, my), 6.46 (111, my), 6.10 (111, my), 5.58 (111, my),
4.45 （111, 내）, 4.27 （111, 내）, 3.82 （ 예）, 3.75 - 3.52 （111, 예）, 2.86 （（!, / = 4.7 예）, 2.38 （111, 내）, 2.29 - 2.11 （111, 개）, 2.01 （111, 仰）, 1.90 - 1.80 （111, 래）, 1.77 - 1.68 （111, 래）, 1.59 （加 ， 래）, 1.50 （111,
Figure imgf000068_0003
4.45 (111, within), 4.27 (111, within), 3.82 (example), 3.75 - 3.52 (111, example), 2.86 ((!, / = 4.7 example), 2.38 (111, within), 2.29 - 2.11 ( 111, pcs), 2.01 (111, 仰), 1.90 - 1.80 (111, rae), 1.77 - 1.68 (111, rae), 1.59 (加 , rae), 1.50 (111,
Figure imgf000068_0003
<실시예 22> 2-（（2-（（2 -메톡시- 4-（（5-（몰포린- 4 -카보닐）아다만탄- 2- 일）아미노）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）-成 3 - 다이메틸벤즈아마이드의 제조 （화합물 22）
Figure imgf000068_0004
<Example 22> 2-((2-((2-methoxy-4-((5-(morpholine-4-carbonyl)adamantan-2-yl)amino)phenyl)amino)-5- Preparation of (trifluoromethyl)pyrimidin-4-yl)amino)-produced 3-dimethylbenzamide (Compound 22)
Figure imgf000068_0004
[단계 1] 4-（（3 -메톡시- 4 -나이트로페닐）아미노）아다만테인- 1 -카복실산 메틸의 제조 2021/111311 ?01/162020/061350
Figure imgf000069_0001
실시예 1 의 단계 1 에서 <3 « 4 -아미노아다만탄- 1 -올 대신에 4 - 아미노아다만 테인- 1 -카복실산 메틸을 사용하여 실시예 1과 동일한 방법으로 표제 화합물을 합성하였다. [Step 1] Preparation of 4-((3-methoxy-4-nitrophenyl)amino)adamantane-1-methyl carboxylate 2021/111311 ?01/162020/061350
Figure imgf000069_0001
In Step 1 of Example 1, the title compound was synthesized in the same manner as in Example 1, using methyl 4-aminoadamantane-1-carboxylate instead of <3 « 4-aminoadamantan-1-ol.
［단계 2］ 4-（（4 -아미노- 3 -메톡시페닐）아미노）아다만테인- 1 -카복실산 메틸의 제조
Figure imgf000069_0002
실시예 1 의 단계 2 에서 （ ^/^« ^-（（크-메톡시-간- 나이트로 페닐）아미노）아다만탄- 1 -올 대신에 4-（（3 -메톡시- 4- 나이트로 페닐）아미노）아다만테인- 1 -카복실산 메틸을 사용하여 실시예 1과 동일한 방법으로 표제 화합물을 합성하였다. [Step 2] Preparation of 4-((4-amino-3-methoxyphenyl)amino)adamantane-1-carboxylate methyl
Figure imgf000069_0002
In step 2 of Example 1, (^/^« ^-((k-methoxy-gan-nitrophenyl)amino)adamantan-1-ol instead of 4-((3-methoxy-4-nitride) The title compound was synthesized in the same manner as in Example 1 using rhophenyl)amino)adamantane-1-carboxylate.
［단계 3］ 4-（（4-（（4 -클로로- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）- 3 -메톡시페닐）아미노）아다만테인- 1 -카복실산 메틸의 제조
Figure imgf000069_0003
메톡시페닐）아미노）아다만탄- 1 -올 대신에 4-( (4 -아미노- 3- 2021/111311 ?01/162020/061350 메톡시페닐）아미노）아다만테인- 1 -카복실산 메틸을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . [Step 3] 4-((4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)adamantane-1-methyl carboxylate manufacture of
Figure imgf000069_0003
Methoxyphenyl)amino)adamantan-1-ol instead of 4-((4-amino-3- 2021/111311 -01/162020/061350 The title compound was synthesized in the same manner as in Example 1 using methyl methoxyphenyl)amino)adamantane-1-carboxylate.
[단계 4] 4-（（3 -메톡시 - 4-（（4-（（2 -메틸- 6-（메틸카바모일）페닐）아미노）- 5- （트라이플루오로메틸）피 리미딘- 2 -일）아미노）페닐）아미노）아다만테인- 1 -카복실산 메틸의 제조
Figure imgf000070_0001
실시 예 1 의 단계 4 에서 （紅 ） -4-（（4-（（4 -클로로- 5-[Step 4] 4-((3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-2) Preparation of -yl)amino)phenyl)amino)adamantane- 1-methyl carboxylate
Figure imgf000070_0001
In step 4 of Example 1, (紅)-4-((4-((4-chloro-5-
（트라이플루오로메틸）피 리미딘- 2 -일）아미노）- 3 -메톡시페닐）아미노）아다만탄- 1 -올 대신에 4-（（4-（（4 -클로로- 5-（트라이플루오로메틸）피 리미딘- 2 -일）아미노）- 3- 메톡시페닐）아미노）아다만테인- 1 -카복실산 메틸을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . (trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)adamantan-1-ol instead of 4-((4-((4-chloro-5-(tri The title compound was synthesized in the same manner as in Example 1 using methyl fluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)adamantane-1-carboxylate.
[단계 5] 4-（（3 -메톡시 - 4-（（4-（（2 -메틸- 6-（메틸카바모일）페닐）아미노）- 5- （트라이플루오로메틸）피 리미딘- 2 -일）아미노）페닐）아미노）아다만테인- 1 -카복실산의 제조
Figure imgf000070_0002
실시 예 17 의 단계 1 에서 4-（3 -메톡시 - 4-（（4-（（2 -메틸- 6-[Step 5] 4-((3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-2) Preparation of -yl)amino)phenyl)amino)adamantane- 1-carboxylic acid
Figure imgf000070_0002
In step 1 of Example 17, 4-(3-methoxy-4-((4-((2-methyl-6-
（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피 리미딘- 2- 2021/111311 ?01/162020/061350 일）아미노）페녹시）아다만테인- 1 -카복실산 메틸 대신에 4-（（3 -메톡시- 4-（（4-（（2- 메틸- 6-（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）페닐）아미노）아다만테인- 1 -카복실산 메틸을 사용하여 실시 예 17 과 동일한 방법으로 표제 화합물을 합성하였다. (methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-2- 2021/111311 ?01/162020/061350 days)amino)phenoxy)adamantane-1-methyl carboxylate instead of 4-((3-methoxy-4-((4-((2-methyl-6-( Methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)amino)adamantane-1-carboxylate The title compound in the same manner as in Example 17 using methyl carboxylate was synthesized.
[단계 6] 2-（（2-（（2 -메톡시- 4-（（5-（몰포린- 4 -카보닐）아다만탄- 2- 일）아미노）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᄊ 3 - 다이메틸벤즈아마이드의 제조
Figure imgf000071_0001
실시 예 19 의 단계 1 에서 4-（3 -메톡시- 4-（（4-（（2 -메틸- 6-[Step 6] 2-((2-((2-methoxy-4-((5-(morpholine-4-carbonyl)adamantan-2-yl)amino)phenyl)amino)-5-( Preparation of trifluoromethyl)pyrimidin-4-yl)amino)- ᄊ 3-dimethylbenzamide
Figure imgf000071_0001
In step 1 of Example 19, 4-(3-methoxy-4-((4-((2-methyl-6-
（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）페녹시）아다만테인- 1 -카복실산 대신에 4-（（3 -메톡시- 4-（（4-（（2 -메틸- 6- （메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）페닐）아미노）아다만테인- 1 -카복실산을 사용하여 실시 예 19 와 동일한 방법으로 표제 화합물을 합성하였다.
Figure imgf000071_0002
6 8.24 （ 111）， 8.19 （ 111）， 7.62 - 7.32 （111, 예）, 7.32 - 7.26 （111, 래）, 6.11 （（!, I = 2.0 ¾ , 내）, 6.03 （ 내）, 5.73 （ 내）, 3.77 （ 예）, 3.68 （111, ）, 3.41 （ 내）, 2.84 （（!, I = 4.7 ¾ , 예）, 2.20 （ 예）, 2.18 - 2.05 （111,
Figure imgf000071_0003
2.00 （ 2¾， 1.90 - 1.79 （111, _ 2021/111311 1^（:1^2020/061350(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenoxy)adamantane-1-carboxylic acid in place of 4-((3-methoxy-4-) ((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)amino)adamantane-1-carboxylic acid The title compound was synthesized in the same manner as in Example 19 using
Figure imgf000071_0002
6 8.24 ( 111), 8.19 ( 111), 7.62 - 7.32 (111, yes), 7.32 - 7.26 (111, lower), 6.11 ((!, I = 2.0 ¾ , within), 6.03 (within), 5.73 (within) ), 3.77 ( ex), 3.68 (111, ), 3.41 (in), 2.84 ((!, I = 4.7 ¾ , ex), 2.20 ( ex), 2.18 - 2.05 (111,
Figure imgf000071_0003
2.00 （ 2¾， 1.90 - 1.79 （111, _ 2021/111311 1^（:1^2020/061350
＜실시예 23 ñ 2-（（2-（（2 -메톡시- 4-（（5-（4 -메틸피페라진- 1 -카보닐）아다만탄_ 2 -일）아미노）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᆻ 3 - 다이메틸벤즈아마이드의 제조 （화합물 23）
Figure imgf000072_0001
<Example 23 - 2-((2-((2-methoxy-4-((5-(4-methylpiperazine-1-carbonyl)adamantane_2-yl)amino)phenyl)amino) - Preparation of 5-(trifluoromethyl)pyrimidin-4-yl)amino)-ᆻ3-dimethylbenzamide (Compound 23)
Figure imgf000072_0001
[단계 1] 2-（（2-（（2 -메톡시- 4-（（5-（4 -메틸피페라진- 1 -카보닐）아다만탄- 2- 일）아미노）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᄊ 3 - 다이메틸벤즈아마이드의 제조
Figure imgf000072_0002
실시 예 22 의 단계 6 에서 몰포린 대신에 1 -메틸피페라진을 사용하여 실시 예 22 와 동일한 방법으로 표제 화합물을 합성하였다.
Figure imgf000072_0003
00013）： 6 8.24 （ 111）， 8.15 （ 111）， 7.37 （111, 예）,[Step 1] 2-((2-((2-methoxy-4-((5-(4-methylpiperazine-1-carbonyl)adamantan-2-yl)amino)phenyl)amino)- Preparation of 5-(trifluoromethyl)pyrimidin-4-yl)amino)-ᄊ 3-dimethylbenzamide
Figure imgf000072_0002
The title compound was synthesized in the same manner as in Example 22 using 1-methylpiperazine instead of morpholine in step 6 of Example 22.
Figure imgf000072_0003
0001 3 ): 6 8.24 ( 111), 8.15 ( 111), 7.37 (111, eg),
7.31 - 7.25 （111, 내）, 6.11 （（!, I = 1.6 ¾ , 내）, 6.03 （ 내）, 5.72 （ 내）, 3.77 （ 예）, 3.71 （ 태）, 3.41 （ 내）, 2.83 （（!, I = 4.6 ¾ , 예）, 2.48 -7.31 - 7.25 (111, within), 6.11 ((!, I = 1.6 ¾ , within), 6.03 (within), 5.72 (within), 3.77 (ex), 3.71 (within), 3.41 (within), 2.83 ( ( !, I = 4.6 ¾ , eg), 2.48 -
2.32 （111, ， 2.29
Figure imgf000072_0004
예）, 2.20
Figure imgf000072_0005
예）, 2.17 - 1.96 （111, 개）, 1.94 - 1.77 （111,2.32 （111, ， 2.29
Figure imgf000072_0004
ex), 2.20
Figure imgf000072_0005
ex), 2.17 - 1.96 (111, pcs), 1.94 - 1.77 (111,
6 6
＜실시예 24＞ 2-（（2-（（2 -메록시- 4-（（5-（（5）-3 -아세트아마이도피롤리딘- 1- 2021/111311 ?01/162020/061350 카보닐）아다만탄- 2 -일）아미노）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4- 일）아미노）- ; 3 -다이메틸벤즈아마이드의 제조 （화합물 24）
Figure imgf000073_0001
<Example 24> 2-((2-((2-meroxy-4-((5-((5)-3-acetamidopyrrolidine-1-) 2021/111311 -01/162020/061350 Carbonyl)adamantan-2-yl)amino)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)- ; Preparation of 3-dimethylbenzamide (Compound 24)
Figure imgf000073_0001
[단계 1] 2-（（2-（（2 -메톡시 - 4-（（5-（（5）-3 -아세트아마이도피롤리딘- 1- 카보닐）아다만탄- 2 -일）아미노）페닐）아미노）- 5-（트라이플루오로메틸）피 리미딘- 4- 일）아미노）- ᄊ 3 -다이메틸벤즈아마이드의 제조
Figure imgf000073_0002
실시 예 22 의 단계 6 에서 몰포린 대신에 （5） -聲（피롤리딘- 3- 일）아세트아마이드를 사용하여 실시 예 22 와 동일한 방법으로 표제 화합물을 합성하였다 .
Figure imgf000073_0003
6 8.24 （ 111）， 8.14 （ 111）， 7.45 - 7.32 （111, 예）, 7.32 - 7.26 （111, 내）, 6.13 （（!, / = 2.2
Figure imgf000073_0005
내）, 6.07 （ 내）, 5.74
Figure imgf000073_0004
내）, 5.62 （111, 내）, 4.42 （111, 내）, 3.86 （ 내）, 3.78 （ 예）, 3.63 （111, 예）, 3.41 （ 내）, 2.83 （（!, I = 4.5 ¾ , 예）, 2.21 （ 예）, 2.18 - 2.03 （111, 애）,[Step 1] 2-((2-((2-methoxy-4-((5-((5)-3-acetamidopyrrolidine-1-carbonyl)adamantan-2-yl)amino )Phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-a 3-dimethylbenzamide
Figure imgf000073_0002
The title compound was synthesized in the same manner as in Example 22 using (5)-聲(pyrrolidin-3-yl)acetamide in step 6 of Example 22 instead of morpholine.
Figure imgf000073_0003
6 8.24 ( 111), 8.14 ( 111), 7.45 - 7.32 (111, eg), 7.32 - 7.26 (111, within), 6.13 ((!, / = 2.2)
Figure imgf000073_0005
within), 6.07 (within), 5.74
Figure imgf000073_0004
within), 5.62 (111, within), 4.42 (111, within), 3.86 (within), 3.78 (eg), 3.63 (111, within), 3.41 (within), 2.83 ((!, I = 4.5 ¾ , yes) ), 2.21 (eg), 2.18 - 2.03 (111, child),
1.98 （111, 태）, 1.83 （111, 611） 1.98 (111, Tae), 1.83 (111, 611)
＜실시예 25 ñ 於（3 -메톡시- 4-（（4-（（2 -메틸- 6-（메틸카바모일）페닐）아미노）_ 2021/111311 ?01/162020/061350 <Example 25 - 於 (3-methoxy-4- ((4- ((2-methyl-6- (methylcarbamoyl) phenyl) amino) _ 2021/111311 ?01/162020/061350
5-（트라이풀루오로메틸）피리미딘- 2 -일）아미노）페닐）-4 -몰포리노아다만테인-1_ 카복사마이드의 제조 （화합물 25）
Figure imgf000074_0001
Preparation of 5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-4-morpholinoadamantane-1_carboxamide (Compound 25)
Figure imgf000074_0001
[단계 1] 聲（3 -메톡시 -4 -나이트로페닐）-4 -옥소아다만테인- 1- 카복사마이드의 제조
Figure imgf000074_0002
[Step 1] Preparation of 聲 (3-methoxy-4-nitrophenyl)-4 -oxoadamantane-1-carboxamide
Figure imgf000074_0002
4 -옥소아다만테인- 1 -카복실산， 3 -메톡시- 4 -나이트로아닐린， 1-4 -oxoadamantane- 1-carboxylic acid, 3-methoxy- 4-nitroaniline, 1-
[비스（다이메틸아미노）메틸렌] -1 1， 2， 3 -트라이아졸로 [4， 5 -別피리디늄 3 -옥사이드 핵사플루오로포스페이트를 ᄊ 다이메틸폼아마이드에 녹인 후 트라이에틸아민을 가하여 5 시간 동안 상온에서 교반하였다. 반응 완료 후 반응 용액에 증류수를 가하고 아세트산 에틸로 추출하였다. 무수 황산 마그네슘으로 건조 후 여과하고 여 액을 농축한 후 컬럼 크로마토그래피로 정제하여 표제 화합물을 얻었다. [Bis (dimethylamino) methylene] -1 1, 2, 3-triazolo [4, 5-別pyridinium 3-oxide hexafluorophosphate was dissolved in ᄊ dimethylformamide, and then triethylamine was added to 5 It was stirred at room temperature for hours. After completion of the reaction, distilled water was added to the reaction solution, followed by extraction with ethyl acetate. It was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain the title compound.
[단계 2] 聲（4 -아미노- 3 -메톡시페닐）- 4 -옥소아다만테인- 1 -카복사마이드의 제조 2021/111311 ?01/162020/061350
Figure imgf000075_0001
실시 예 1 의 단계 2 에서 （ /"/^/^- -（ -메톡시-간- 나이트로페닐）아미노）아다만탄- 1 -올 대신에 聲（3 -메톡시- 4 -나이트로페닐）- 4- 옥소아다만테인- 1 -카복사마이드를 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다. [Step 2] Preparation of 聲 (4-amino-3-methoxyphenyl)- 4-oxoadamantane- 1-carboxamide 2021/111311 ?01/162020/061350
Figure imgf000075_0001
In step 2 of Example 1, 聲(3-methoxy-4-nitrophenyl) instead of (/"/^/^- -(-methoxy-gan- nitrophenyl)amino)adamantan-1-ol )- The title compound was synthesized in the same manner as in Example 1 using 4-oxoadamantane-1-carboxamide.
[단계 3] 聲（4-（（4 -클로로- 5-（트라이플루오로메틸）피리미딘- 2 -일）아미노）_ 3 -메톡시페닐）-4 -옥소아다만테인- 1 -카복사마이드의 제조
Figure imgf000075_0002
실시 예 1 의 단계 3 에서 （ « - -（（간 -아미노- 3_ 메톡시페닐）아미노）아다만탄- 1 -올 대신에 聲（4 -아미노- 3 -메톡시페닐）- 4- 옥소아다만테인- 1 -카복사마이드를 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다. [Step 3] 聲 (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)_3-methoxyphenyl)-4 -oxoadamantane- 1-carboxa manufacture of mide
Figure imgf000075_0002
In step 3 of Example 1, 聲(4-amino-3-methoxyphenyl)-4-oxoa instead of ( «--((liver-amino-3_ methoxyphenyl)amino)adamantan-1-ol The title compound was synthesized in the same manner as in Example 1 using damantane-1-carboxamide.
[단계 4] 聲（3 -메톡시- 4-（（4-（（2 -메틸- 6-（페틸카바모일）페닐）아미노）- 5- （트라이플루오로메틸）피리미딘- 2 -일）아미노）페닐）-4 -옥소아다만테인- 1- 카복사마이드의 제조 2021/111311 ?01/162020/061350
Figure imgf000076_0001
실시 예 1 의 단계 4 에서 （紅 ） -4-（（4-（（4 -클로로- 5-[Step 4] 聲(3-methoxy-4-((4-((2-methyl-6-(ethylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl) Amino) phenyl) -4 -oxoadamantane- 1- Carboxamide production 2021/111311 ?01/162020/061350
Figure imgf000076_0001
In step 4 of Example 1, (紅)-4-((4-((4-chloro-5-
（트라이플루오로메틸）피 리미딘- 2 -일）아미노）- 3 -메톡시페닐）아미노）아다만탄- 1 -올 대신에 聲（4-（（4 -클로로- 5-（트라이플루오로메틸）피 리미딘- 2 -일）아미노）- 3- 메톡시페닐）- 4 -옥소아다만테인- 1 -카복사마이드을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . (trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)adamantan-1-ol instead of 聲(4-((4-chloro-5-(trifluoro) The title compound was synthesized in the same manner as in Example 1 using methyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)-4-oxoadamantane-1-carboxamide.
[단계 5] 聲（3 -메톡시 - 4-（（4-（（2 -메틸- 6-（메틸카바모일）페닐）아미노）- 5- （트라이플루오로메틸）피 리미딘- 2 -일）아미노）페닐）-4 -몰포리노아다만테인- 1- 카복사마이드의 제조
Figure imgf000076_0002
실시 예 12 의 단계 1 에서 2-（（2-（（2-메톡시 -4-（（4-옥소아다만탄-1_ 일）옥시）페닐）아미노）- 5-（트라이플루오로메틸）피 리미딘- 4 -일）아미노）- ᄊ 3_ 다이메틸벤즈아마이드 대신에 （3 -메톡시 - 4-（（4-（（2 -메틸- 6-[Step 5] 聲(3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl )Amino)phenyl)-4-morpholinoadamantane-1-carboxamide
Figure imgf000076_0002
2-((2-((2-methoxy-4-((4-oxoadamantan-1_yl)oxy)phenyl)amino)-5-(trifluoromethyl)p in step 1 of Example 12 rimidin-4-yl)amino)- ᄊ 3_ instead of dimethylbenzamide (3-methoxy-4-((4-((2-methyl-6-)
（페틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피 리미딘- 2 -일）아미노）페닐）_(Pethylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)_
4 -옥소아다만테인- 1 -카복사마이드를 사용하여 실시 예 12 와 동일한 방법으로 표제 화합물을 합성하였다 . The title compound was synthesized in the same manner as in Example 12 using 4-oxoadamantane-1-carboxamide.
¾ » （400 ， 0[13）: 6 8.40 （ 페， 8.29 （ 페， 7.69 （ 페， 2021/111311 ?01/162020/061350¾ » （400 ， 0[1 3 ]: 6 8.40 （ Pe， 8.29 （ Pe， 7.69 （ Pe， 2021/111311 ?01/162020/061350
7.53 （ 내）, 7.41 （111, 래）, 7.32 （ᄂ / = 7.9 ¾ , 내）, 7.19 （ 내）, 6.34 （ 내）, 6.01 （ 내）, 3.86 （ 예）, 3.75 （111, 태）, 2.88 （111, 예）, 2.45 （ 예）, 2.21 （ 예）, 2.16 - 2.01 （111, 仰）, 1.93 （111, 태）, 1.58 （ 예）, 1.40 （111, ¾） 7.53 (within), 7.41 (111, lower), 7.32 (ᄂ / = 7.9 ¾ , within), 7.19 (within), 6.34 (within), 6.01 (within), 3.86 (eg), 3.75 (111, within), 2.88 (111, Yes), 2.45 (Yes), 2.21 (Yes), 2.16 - 2.01 (111, 仰), 1.93 (111, Tae), 1.58 (Example), 1.40 (111, ¾)
＜실시예 26 ñ 聲（3 -메톡시- 4-（（4-（（2 -메틸- 6-（메틸카바모일）페닐）아미노）_ 5-（트라이플루오로메틸）피리미딘- 2 -일）아미노）페닐）_4_（4 -메틸피페라진- 1- 일）아다만테인- 1 -카복사마이드의 제조 （화합물 26）
Figure imgf000077_0001
<Example 26 ñ 聲 (3-methoxy-4- ((4- ((2-methyl-6- (methylcarbamoyl) phenyl) amino) _ 5- (trifluoromethyl) pyrimidin-2-yl )Amino)phenyl)_4_(4-methylpiperazin-1-yl)adamantane-1-carboxamide (Compound 26)
Figure imgf000077_0001
[단계 1] 聲（3 -메톡시- 4-（（4-（（2 -메틸- 6-（메틸카바모일）페닐）아미노）- 5- （트라이플루오로메틸）피리미딘- 2 -일）아미노）페닐）- 4-（4 -메틸피페라진- 1- 일）아다만테인- 1 -카복사마이드의 제조
Figure imgf000077_0002
실시 예 25 의 단계 5 에서 몰포린 대신에 4 -메틸피페라진을 사용하여 실시 예 25 와 동일한 방법으로 표제 화합물을 합성하였다. [Step 1] 聲(3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl) Preparation of amino)phenyl)-4-(4-methylpiperazin-1-yl)adamantane-1-carboxamide
Figure imgf000077_0002
The title compound was synthesized in the same manner as in Example 25 using 4-methylpiperazine instead of morpholine in step 5 of Example 25.
¾ » （400 ， 0[13）: 6 8.39 ， 페， 8.29 ， 페， 7.69 ， 페， 7.53 （ 내）, 7.40 （111, 래）, 7.35 - 7.29 （111, 내）, 7.18 （ 내）, 6.34 （ 내）, 2021/111311 ?01/162020/061350¾ » (400 , 0[1 3 ): 6 8.39 , pe, 8.29 , pe, 7.69 , pe, 7.53 (in), 7.40 (111, rae), 7.35 - 7.29 (111, in), 7.18 (in), 6.34 (my), 2021/111311 ?01/162020/061350
6.00 （ 내）, 3.86 （ 해）, 2.87 （（!, / = 4.8
Figure imgf000078_0001
예）, 2.48 （ 태）, 2.30 （ 예）, 2.24 （ 내）, 2.21 （ 예）, 2.07 （111, 해）, 1.92 （111, 예）, 1.68 （ 개）,6.00 ( within), 3.86 (year), 2.87 ((!, / = 4.8)
Figure imgf000078_0001
Ex), 2.48 (Ta), 2.30 (Ex), 2.24 (In), 2.21 (Ex), 2.07 (111, Year), 1.92 (111, Ex), 1.68 (P),
1.38 （111, 2 1.38 (111, 2
＜실시예 27＞ /· 2 ）-4-（（幻- 3 -아세트아마이도피롤리딘-!-일）- ·（3- 메톡시- 4-（（4-（（2 -메틸- 6-（메틸카바모일）페닐）아미노）- 5- （트라이플루오로메틸）피리미딘- 2 -일）아미노）페닐）아다만테인- 1 -카복사마이드의 제조 （화합물 27）
Figure imgf000078_0002
<Example 27> // 2)-4-((幻-3 -acetamidopyrrolidin-!-yl)-(3-methoxy-4-((4-((2-methyl-6-) Preparation of (methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)adamantane-1-carboxamide (Compound 27)
Figure imgf000078_0002
[단계 1] （ ＜ ）-4-（（5）-3 -아세트아마이도피롤리딘- 1 -일）-聲（3 -메톡시- 4- （（4-（（2 -메틸- 6-（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）페닐）아다만테인- 1 -카복사마이드의 제조
Figure imgf000078_0003
실시 예 25 의 단계 5 에서 몰포린 대신에 （5） -聲（피롤리딘- 3- 일）아세트아마이드를 사용하여 실시 예 25 와 동일한 방법으로 표제 화합물을 2021/111311 ?01/162020/061350 합성하였다. [Step 1] ( < )-4-((5)-3 -acetamidopyrrolidin- 1-yl)-聲(3-methoxy-4- ((4-((2-methyl-6- ( Preparation of methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)adamantane-1-carboxamide
Figure imgf000078_0003
In step 5 of Example 25, the title compound was prepared in the same manner as in Example 25, using (5)-聲(pyrrolidin-3-yl)acetamide instead of morpholine. 2021/111311 ?01/162020/061350 Synthesized.
¾ » （400 ， 0[13）: 6 8.45 ， 페， 8.28 ， 페， 7.69 ， 페， 7.52 （ 내）, 7.46 - 7.28 （111, 태）, 6.23 （ 내）, 6.06 （ 내）, 4.59 （ 내）, 3.85 （ 예）, 2.85 （（!, I = 4.7 ¾ , 예）, 2.46 （111, 태）, 2.26 - 2.08 （111, 仰）, 2.09 - 1.83 （111, 1211） , 1.71 （111, ¾） ¾ » (400 , 0[1 3 ): 6 8.45 , pe, 8.28 , pe, 7.69 , pe, 7.52 (in), 7.46 - 7.28 (111, tae), 6.23 (in), 6.06 (in), 4.59 ( within), 3.85 ( ex), 2.85 ((!, I = 4.7 ¾ , ex), 2.46 (111, Tae), 2.26 - 2.08 (111, 仰), 2.09 - 1.83 (111, 1211) , 1.71 (111, ¾)
<실시예 28> 0/5）-4-（（5）-3-아세트아마이도피롤리딘-1-일）-聲（3-메톡시- 4-（（4-（（2 -메틸- 6-（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）페닐）아다만테인- 1 -카복사마이드의 제조 （화합물 28）
Figure imgf000079_0001
<Example 28> 0/5)-4-((5)-3-acetamidopyrrolidin-1-yl)-聲(3-methoxy-4-((4-((2-methyl-6) Preparation of -(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)adamantane-1-carboxamide (Compound 28)
Figure imgf000079_0001
[단계 1] （ 5）-4-（（5）-3-아세트아마이도피롤리딘-1-일）-聲（3-메톡시-4_[Step 1] (5)-4-((5)-3-acetamidopyrrolidin-1-yl)-聲(3-methoxy-4_
（（4-（（2 -메틸- 6-（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）페닐）아다만테인- 1 -카복사마이드의 제조
Figure imgf000079_0002
실시 예 25 의 단계 5 에서 몰포린 대신에 （5） -聲（피롤리딘- 3 - 2021/111311 ?01/162020/061350 일）아세트아마이드를 사용하여 실시예 25 와 동일한 방법으로 표제 화합물을 합성하였다. ((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)adamantane-1-carboxamide manufacture of
Figure imgf000079_0002
Instead of morpholine in step 5 of Example 25, (5) -聲 (pyrrolidine-3 - 2021/111311 - 01/162020/061350 days) The title compound was synthesized in the same manner as in Example 25 using acetamide.
¾ » （400 ， 0犯13）: 6 8.43 ， 페， 8.29 ， 페， 7.69 ， 페， 7.50 （ 내）， 7.40 （111, 래）, 7.31 （ᄂ I = 7.4 ¾ , 내）, 7.20 （ 내）, 6.35 （ 내）, 6.07 （（!, I = 5.0 ¾ , 내）, 4.49 （ 내）, 3.86 （ 예）, 2.87 （（!, I = 4.9 ¾ , 해）, 2.55
Figure imgf000080_0001
페 , 2.29
Figure imgf000080_0002
페 , 2.24 - 1.87 （111, ■ , 1.70
Figure imgf000080_0003
1.45¾ » （400 ， 0犯1 3 ）: 6 8.43 , pe, 8.29 , pe, 7.69 , pe, 7.50 (within), 7.40 (111, rae), 7.31 (ᄂ I = 7.4 ¾ , within), 7.20 (within) ), 6.35 ( within), 6.07 ((!, I = 5.0 ¾ , within), 4.49 (within), 3.86 (ex), 2.87 ((!, I = 4.9 ¾ , year), 2.55
Figure imgf000080_0001
P , 2.29
Figure imgf000080_0002
P , 2.24 - 1.87 （111, ■ , 1.70
Figure imgf000080_0003
1.45
（（1, 2 (（1, 2
＜실시예 29 ñ 4 -하이드록시 - ·（3 -메록시 -4-（（4-（（2 -메틸- 6-<Example 29 - 4-hydroxyl - (3-meroxy-4- ((4- ((2-methyl-6-)
（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）페닐）아다만테인- 1 -카복사마이드의 제조 （화합물 29）
Figure imgf000080_0004
시 -聲（3 -메톡시 -4-（（4-（（2 -메틸- 6-Preparation of (methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)adamantane-1-carboxamide (Compound 29)
Figure imgf000080_0004
Shi -聲（3-methoxy-4-（（4-（（2-methyl-6-
（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）페닐）아다만테인- 1 -카복사마이드의 제조
Figure imgf000080_0005
2021/111311 ?01/162020/061350 실시예 11 의 단계 1 에서 2-（（2-（（2-메톡시-4-（（4-옥소아다만탄-1_ 일）옥시）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᄊ3_ 다이메틸벤즈아마이드 대신에 （3 -메톡시- 4-（（4-（（2 -메틸- 6-Preparation of (methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)adamantane-1-carboxamide
Figure imgf000080_0005
2021/111311 - 01/162020/061350 2-((2-((2-methoxy-4-((4-oxoadamantan-1_yl)oxy)phenyl)amino)- in step 1 of Example 11 5-(trifluoromethyl)pyrimidin-4-yl)amino)- ᄊ3_ instead of dimethylbenzamide (3-methoxy-4-((4-((2-methyl-6-)
（페틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2 -일）아미노）페닐）_ (Pethylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)_
4 -옥소아다만테인- 1 -카복사마이드를 사용하여 실시예 11과 동일한 방법으로 표제 화합물을 합성하였다. The title compound was synthesized in the same manner as in Example 11 using 4-oxoadamantane-1-carboxamide.
¾ » （400 ， 0-（16）: 6 9.10 ， 페， 8.96 - 8.85 （111, 페, 8.27 - 8.20 （111, 래）, 7.90 （ 내）, 7.41 - 7.23 （111, 해）, 6.86 （加 내）, 4.59 （111, 페, 3.69 예）, 3.68 - 3.54 （111, 페, 2.63 （（1, /= 4.5, 예）, 2.15 - 1.96 （111, 해）, 1.88 - 1.74 （111, 개）, 1.68 （111, 내）, 1.56 （111, 내）, 1.35 - 1.27 （111, ¾） ¾ » （400 ， 0-（1 6 ）: 6 9.10 ， Pe, 8.96 - 8.85 （111, Pe, 8.27 - 8.20 (111, Rae), 7.90 ( My), 7.41 - 7.23 (111, Year), 6.86 (加), 4.59 (111, pes, 3.69 ex), 3.68 - 3.54 (111, pes, 2.63 ((1, /= 4.5, eg), 2.15 - 1.96 (111, year), 1.88 - 1.74 (111, ea) ), 1.68 (111, within), 1.56 (111, within), 1.35 - 1.27 (111, ¾)
<실시예 30> （ 2/25）-4-（（5）-3 -아미노피롤리딘- 1 -일）- ·（3 -메특시- 4-（（4- （（2 -메틸- 6-（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）페닐）아다만테인- 1 -카복사마이드의 제조 （화합물 30）
Figure imgf000081_0001
<Example 30> (2/25)-4-((5)-3 -aminopyrrolidin-1-yl)-·(3-methoxy-4-((4-((2-methyl-6) Preparation of -(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)adamantane-1-carboxamide (Compound 30)
Figure imgf000081_0001
[단계 1] 此/ -뷰틸 （（35）-1-（（ 7 ）-5-（（3 -메톡시- ^（（^（（ᅡ메틸내- ¬메틸카바모일세닐ᅵ아미노ᅡ크 트라이플루오로메틸ᅵ피리미딘 - 일 아미노ᅵ페닐）카바모일）아다만탄- 2 -일）피롤리딘- 3 -일）카바메이트의 제조 2021/111311 ?01/162020/061350
Figure imgf000082_0001
실시 예 25 의 단계 5 에서 몰포린 대신에 / -뷰틸 （ 5） -피롤리딘- 3- 일카바메이트를 사용하여 실시 예 25 와 동일한 방법으로 표제 화합물을 합성하였다 . [Step 1] 此/-butyl ((35)-1-((7)-5-((3-methoxy-^((^((in methyl- ¬methylcarbamoylcenylᅵamino) trifluoro) Preparation of romethyl-pyrimidin-ylamino-phenyl)carbamoyl)adamantan-2-yl)pyrrolidin-3-yl)carbamate 2021/111311 ?01/162020/061350
Figure imgf000082_0001
The title compound was synthesized in the same manner as in Example 25 using /-butyl(5)-pyrrolidin-3-ylcarbamate in step 5 of Example 25 instead of morpholine.
[단계 2] （ 幻 ）-4-（（5）-3 -아미노피롤리딘- 1 -일）-聲（3 -메톡시- 4-（（4- （（2 -메틸- 6-（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피 리미딘- 2- 일）아미노）페닐）아다만테인- 1 -카복사마이드의 제조
Figure imgf000082_0002
상기 단계 1 에서 제조한 기-뷰틸 （（35）_1_（（ £0-5-（（3 -메톡시 - 4-（（4- （（2 -메틸- 6-（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피 리미딘- 2- 일）아미노）페닐）카바모일）아다만탄- 2 -일）피롤리딘- 3 -일）카바메이트를 4 염산 다이옥세인 용액에 녹인 후 상온에서 교반하였다 . 반응 종결을 孔[：로 확인한 후 반응 용액에 어 포화수용액을 가하고 아세트산 에틸로 추출하였다 . 무수 황산 마그네슘으로 건조 후 여과하고 여 액을 농축한 후 컬럼 크로마토그래피로 정제하여 표제 화합물을 얻었다 . [Step 2] (幻)-4-((5)-3 -aminopyrrolidin-1-yl)-聲(3-methoxy-4-((4-((2-methyl-6-(methyl) Preparation of carbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)adamantane-1-carboxamide
Figure imgf000082_0002
Group-butyl ((35)_1_((£0-5-((3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino) prepared in step 1 above) )-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)carbamoyl)adamantan-2-yl)pyrrolidin-3-yl)carbamate in dioxane tetrahydrochloride solution After dissolving, the mixture was stirred at room temperature. After confirming the completion of the reaction with 孔[:, a saturated aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. It was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain the title compound.
¾ » （400 ， 0[13）: 6 8.46 ， 페， 8.30 ， 페， 7.70 ， 페， 7.53 （ 내）, 7.46 - 7.20 （111, 태）, 6.37 （111, 내）, 6.14 （111, 내）, 3.52 （ 내）, 3.86 （ 예）, 2.87 （（1, I = 4.8 예）, 2.85 - 1.25 （111, 2 2021/111311 ?01/162020/061350 ¾ » (400 , 0[1 3 ): 6 8.46 , pe, 8.30 , pe, 7.70 , pe, 7.53 (in), 7.46 - 7.20 (111, tae), 6.37 (111, in), 6.14 (111, in) ), 3.52 (within), 3.86 (example), 2.87 ((1, I = 4.8 example), 2.85 - 1.25 (111, 2 2021/111311 ?01/162020/061350
<실시예 31> /섟-4-（（幻- 3 -아미노피롤리딘-]-일）-세메톡시- 4-（（4-（（2_ 메틸- 6-（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）페닐）아다만테인- 1 -카복사마이드의 제조 （화합물 31）
Figure imgf000083_0001
<Example 31> /z-4-((幻-3-aminopyrrolidin-]-yl)-semethoxy-4-((4-((2_methyl-6-(methylcarbamoyl)phenyl)amino )- Preparation of 5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)adamantane-1-carboxamide (Compound 31)
Figure imgf000083_0001
[단계 1] 此/ -뷰틸 （（35）-1-（（ 7 ）-5-（（3 -메톡시- ^（（^（（ᅡ메틸내- ¬메틸카바모일세닐ᅵ아미노ᅡ크 트라이플루오로메틸ᅵ피리미딘 - 일 아미노ᅵ페닐）카바모일）아다만탄- 2 -일）피롤리딘- 3 -일）카바메이트의 제조
Figure imgf000083_0002
실시예 25 의 단계 5 에서 몰포린 대신에 / -뷰틸 （5） -피롤리딘- 3- 일카바메이트를 사용하여 실시예 25와동일한 방법으로표제 화합물을 합성하였다. [Step 1] 此/-butyl ((35)-1-((7)-5-((3-methoxy-^((^((in methyl- ¬methylcarbamoylcenylᅵamino) trifluoro) Preparation of romethyl-pyrimidin-ylamino-phenyl)carbamoyl)adamantan-2-yl)pyrrolidin-3-yl)carbamate
Figure imgf000083_0002
The title compound was synthesized in the same manner as in Example 25, using /-butyl (5)-pyrrolidin-3-ylcarbamate in step 5 of Example 25 instead of morpholine.
[단계 2] （ ）-4-（（5）-3 -아미노피롤리딘- 1 -일）-聲（3 -메톡시- 4-（（4-（（2_ 메틸- 6-（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）페닐）아다만테인- 1 -카복사마이드의 제조 2021/111311 ?01/162020/061350
Figure imgf000084_0001
상기 단계 1 에서 제조한 此/ -뷰틸 （（35）-1-（（ ）-5-（（3 -메톡시 - 4-（（4- （（2 -메틸- 6-（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피 리미딘- 2- 일）아미노）페닐）카바모일）아다만탄- 2 -일）피롤리딘- 3 -일）카바메이트를 4 염산 다이옥세 인 용액에 녹인 후 상온에서 교반하였다 . 반응 종결을 孔[：로 확인한 후 반응 용액에 어 포화수용액을 가하고 아세트산 에틸로 추출하였다 . 무수 황산 마그네슘으로 건조 후 여과하고 여 액을 농축한 후 컬럼 크로마토그래피로 정제하여 표제 화합물을 얻었다 . [Step 2] ( )-4-((5)-3 -aminopyrrolidin-1-yl)-聲(3-methoxy-4-((4-((2_methyl-6-(methylcarbamoyl) Preparation of )phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)adamantane-1-carboxamide 2021/111311 ?01/162020/061350
Figure imgf000084_0001
此/-butyl ((35)-1-(()-5-((3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl) prepared in step 1) )amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)carbamoyl)adamantan-2-yl)pyrrolidin-3-yl)carbamate with tetrahydrochloride dioxane It was dissolved in a phosphorus solution and stirred at room temperature. After confirming the completion of the reaction with 孔[:, a saturated aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. It was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain the title compound.
¾ » （400 ， 0[13）: 5 8.45 （ 페， 8.29 （ 페， 7.70 （ 페，¾ » （400 ， 0[1 3 ]: 5 8.45 （ Pe， 8.29 （ Pe， 7.70 （ Pe，
7.53 （ 내）, 7.46 - 7.20 （111, 태）, 6.36 （111, 내）, 6.14 （111, 내）, 3.52 （ 내）,7.53 (inner), 7.46 - 7.20 (111, older), 6.36 (111, inner), 6.14 (111, inner), 3.52 (inner),
3.86 （ 예）, 2.87 （（1, / = 4.8
Figure imgf000084_0002
예）, 2.85 - 1.25 （111, 2 3.86 (Example), 2.87 ((1, / = 4.8)
Figure imgf000084_0002
ex), 2.85 - 1.25 (111, 2
<실시예 32> 2-（（2-（（4-（1-（（ /¾/7£!）_5 -하이드록시아다만탄- 2 -일）피페리딘- 4 -일）-2 -메특시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）-/ V, 3 - 다이 메틸벤즈아마이드의 제조 （화합물 32） 2021/111311 ?01/162020/061350
Figure imgf000085_0001
<Example 32> 2-((2-((4-(1-(( /¾/7£ !) ) _ 5 -hydroxyadamantan-2 -yl)piperidin-4-yl)-2 -methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)- / V, 3 - Preparation of dimethylbenzamide (Compound 32) 2021/111311 ?01/162020/061350
Figure imgf000085_0001
[단계 1] 2-（（2-（（4-（1-（（紅 5）-5 -하이드록시아다만탄- 2 -일）피페리딘- 4- 일）-2 -메톡시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᄊ 3 - 다이메틸벤즈아마이드의 제조
Figure imgf000085_0002
[Step 1] 2-((2-((4-(1-((紅 5)-5-hydroxyadamantan-2-yl)piperidin-4-yl)-2-methoxyphenyl) Amino) - 5- (trifluoromethyl) pyrimidin - 4-yl) amino) - ᄊ 3 - Preparation of dimethylbenzamide
Figure imgf000085_0002
（트라이플루오로메틸）피리미딘- 2 -일）아미노）- 3 -메톡시페닐）아미노）아다만탄- 1 -올 대신에 （紅 ）-4-（4-（4-（（4 -클로로- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）- 3 -메톡시페닐）피페리딘- 1 -일）아다만탄- 1 -올을 사용하여 실시예 1 과 동일한 방법으로 표제 화합물을 합성하였다. （400 ■¾ , 00013）： 6 8.38 （ 내）, 8.29 （ 내）, 7.69 （加 내）, 7.46 - 7.28 （111, 예）, 6.70 （（!, / = 7.0 ¾ , 내）, 6.41 （加 내）, 6.06 （加 페 , 5.98 （ 페 , 3.85 （ 예）, 3.09 （111, 2¾， 2.89 （111, 2¾， 2.86 （（!，
Figure imgf000085_0003
(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)adamantan-1-ol instead of (紅)-4-(4-(4-((4-chloro) - 5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-1-yl)adamantan-1-ol in the same manner as in Example 1 The title compound was synthesized. (400 ¾ , 0001 3 ): 6 8.38 (within), 8.29 (within), 7.69 (within), 7.46 - 7.28 (111, eg), 6.70 ((!, / = 7.0 ¾ , within), 6.41 (加), 6.06 （加 peso , 5.98 （ peso , 3.85 （ eg ）, 3.09 （111, 2¾, 2.89 （111, 2¾, 2.86 （（!，
Figure imgf000085_0003
4.9 ¾ , 예）, 2.72 - 2.59 （111, 래）, 2.53 （111, 내）, 2.37 （111, 내）, 2.31 （111,
Figure imgf000085_0004
4.9 ¾ , eg), 2.72 - 2.59 (111, lower), 2.53 (111, inner), 2.37 (111, inner), 2.31 (111,
Figure imgf000085_0004
2.24 （111, 1¾， 2.22 （ 예）， 2.13 - 1.20 （111, 1311） 2021/111311 ?01/162020/061350 2.24 (111, 1¾, 2.22 (eg), 2.13 - 1.20 (111, 1311) 2021/111311 ?01/162020/061350
<실시예 33> 2-（（2-（（4-（ 1-（（ 0/）-5 -하이드록시아다만탄- 2 -일）피페리딘- 4- 일）-2 -메톡시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）-/ V, 3- 다이메틸벤즈아마이드의 제조 （화합물 33）
Figure imgf000086_0001
<Example 33> 2-((2-((4-(1-((0/)-5-hydroxyadamantan-2-yl)piperidin-4-yl)-2-methoxyphenyl )Amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)- / V, 3-dimethylbenzamide (Compound 33)
Figure imgf000086_0001
[단계 1] 2-（（2-（（4-（1-（（ 5）-5-하이드록시아다만탄-2-일）피페리딘-4- 일）-2 -메톡시페닐）아미노）- 5-（트라이플루오로메틸）피 리미딘- 4 -일）아미노）- ᄊ 3 - 다이메틸벤즈아마이드의 제조
Figure imgf000086_0002
실시 예 1 의 단계 4 에서 （紅 ） -4-（（4-（（4 -클로로- 5-[Step 1] 2-((2-((4-(1-((5)-5-hydroxyadamantan-2-yl)piperidin-4-yl)-2-methoxyphenyl)amino )- 5- (trifluoromethyl) pyrimidin-4-yl) amino) - ᄊ 3 - Preparation of dimethylbenzamide
Figure imgf000086_0002
In step 4 of Example 1, (紅)-4-((4-((4-chloro-5-
（트라이플루오로메틸）피 리미딘- 2 -일）아미노）- 3 -메톡시페닐）아미노）아다만탄- 1 -올 대신에 （ ）-4-（4-（4-（（4 -클로로- 5-（트라이플루오로메틸）피 리미딘- 2 -일）아미노）_ 3 -메톡시페닐）피페리딘- 1 -일）아다만탄- 1 -올을 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . （400 ■¾ , 00013）： 6 8.38 （ 내）, 8.29 （ 내）, 7.69 （加 ， 2021/111311 ?01/162020/061350 내）, 7.46 - 7.28 （111, 예）, 6.70 （（!, / = 7.0 ¾ , 내）, 6.41 （加 내）, 6.06 （加 내）, 5.99 （ 내）, 3.85 （ 예）, 3.09 （111, 래）, 2.89 （111, 래）, 2.87 （（!, / = 4.9 ¾ , 예）, 2.72 - 2.59 （111, 래）, 2.53 （111, 내）, 2.38 （111, 내）, 2.31 （111, 내）, 2.24 （111, 내）, 2.21 （ 예）, 2.13 - 1.20 （111, 1311） (trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)adamantan-1-ol instead of ( )-4-(4-(4-((4-chloro) - The same method as in Example 1 using 5-(trifluoromethyl)pyrimidin-2-yl)amino)_3-methoxyphenyl)piperidin-1-yl)adamantan-1-ol to synthesize the title compound. (400 ¾ , 0001 3 ): 6 8.38 (inside), 8.29 (inside), 7.69 (加 , 2021/111311 ?01/162020/061350), 7.46 - 7.28 (111, eg), 6.70 ((!, / = 7.0 ¾ , within), 6.41 (within 加), 6.06 (within 加), 5.99 (within) , 3.85 (Example), 3.09 (111, Rae), 2.89 (111, Rae), 2.87 ((!, / = 4.9 ¾ , Ex), 2.72 - 2.59 (111, Rae), 2.53 (111, Inner), 2.38 (111, within), 2.31 (111, within), 2.24 (111, within), 2.21 (eg), 2.13 - 1.20 (111, 1311)
<실시예 34> 2-（（2-（（4-（ 1-（（ /해 -크 -하이드록시아다만탄- 2 -일）피페리딘_ 4 -일）-2 -메특시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- 3- 메틸벤즈아마이드의 제조 （화합물 34）
Figure imgf000087_0001
<Example 34> 2-((2-((4-(1-((/H-K-hydroxyadamantan-2-yl)piperidin_4-yl)-2 -methoxyphenyl) Preparation of amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-3-methylbenzamide (Compound 34)
Figure imgf000087_0001
[단계 1] 2-（（2-（（4-（1-（（紅 5）-5 -하이드록시아다만탄- 2 -일）피페리딘- 4- 일）-2 -메톡시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- 3- 메틸벤즈아마이드의 제조
Figure imgf000087_0002
실시 예 32 의 단계 1 에서 2 -아미노-水 3 -다이메틸벤즈아마이드 대신에 2 - 아미노- 3 -메틸벤즈아마이드를 사용하여 실시 예 32 와 동일한 방법으로 표제 화합물을 2021/111311 ?01/162020/061350 합성하였다. （400 ■¾， 犯13）: 6 8.39 （ 111）， 8.30 （ 111）, 7 70 （ ， 내）, 7.54 - 7.43 （111, 래）, 7.35 （111, 내）, 6.70 （ 내）, 6.41 （加 페 , 6.04 （加 내）, 5.57 （ 내）, 3.85 （ 예）, 3.09 （111, 래）, 2.87 （111, ¾） 2.63 （111, 래）, 2.53 （111, 내）, 2.37 （111, 내）, 2.31 （111, 내）, 2.23 （ 예）, 2.13 - 1.20 （111, ） [Step 1] 2-((2-((4-(1-((紅 5)-5-hydroxyadamantan-2-yl)piperidin-4-yl)-2-methoxyphenyl) Amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-3-methylbenzamide
Figure imgf000087_0002
The title compound was prepared in the same manner as in Example 32 using 2-amino-3-methylbenzamide in Step 1 of Example 32 instead of 2-amino-water 3-dimethylbenzamide. 2021/111311 ?01/162020/061350 Synthesized. (400 ¾, 犯1 3 ): 6 8.39 ( 111), 8.30 ( 111), 7 70 ( , in), 7.54 - 7.43 (111, in), 7.35 (111, in), 6.70 (in), 6.41 （加 Pe, 6.04 (inner), 5.57 (inner), 3.85 (ex), 3.09 (111, lower), 2.87 (111, ¾) 2.63 (111, lower), 2.53 (111, inner), 2.37 (111) , within), 2.31 (111, within), 2.23 (eg), 2.13 - 1.20 (111, )
<실시예 35> 2-（（2-（（4-（ 1-（（ 5）-5 -하이드록시아다만탄- 2 -일）피페리딘- 4- 일）-2 -메특시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- 3- 메틸벤즈아마이드의 제조 （화합물 35）
Figure imgf000088_0001
<Example 35> 2-((2-((4-(1-((5)-5-hydroxyadamantan-2-yl)piperidin-4-yl)-2-methoxyphenyl) Preparation of amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-3-methylbenzamide (Compound 35)
Figure imgf000088_0001
[단계 1] 2-（（2-（（4-（1-（（ 5）-5-하이드록시아다만탄-2-일）피페리딘-4_ 일）-2 -메톡시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- 3- 메틸벤즈아마이드의 제조
Figure imgf000088_0002
2021/111311 ?01/162020/061350 실시 예 33 의 단계 1 에서 2 -아미노-水 3 -다이메틸벤즈아마이드 대신에 2 - 아미노- 3 -메틸벤즈아마이드를 사용하여 실시 예 33 과 동일한 방법으로 표제 화합물을 합성하였다. （400 ■¾ , 00013）： 6 8.41 （ 내）, 8.30 （ 내）, 7.70 （加 내）, 7.53 - 7.44 （111, 래）, 7.35 （ᄂ I = 7.6 ¾ , 내）, 6.69 （ 내）, 6.41 （加 내）, 6.03 （加 내）, 5.59 （ 내）, 3.85 （ 예）, 3.09 （111, 래）, 2.87 （111, 래）, 2.63 （111, 래）, 2.53 （111, 내）, 2.37 （111, 내）, 2.31 （111, 내）, 2.23 （ 예）, 2.13 -[Step 1] 2-((2-((4-(1-((5)-5-hydroxyadamantan-2-yl)piperidin-4_yl)-2-methoxyphenyl)amino) - Preparation of 5-(trifluoromethyl)pyrimidin-4-yl)amino)-3-methylbenzamide
Figure imgf000088_0002
2021/111311 - 01/162020/061350 The title compound in the same manner as in Example 33, using 2-amino-3-methylbenzamide instead of 2-amino-water 3-dimethylbenzamide in Step 1 of Example 33 was synthesized. (400 ¾ , 0001 3 ): 6 8.41 (inner), 8.30 (inner), 7.70 (inner), 7.53 - 7.44 (111, lower), 7.35 (ᄂ I = 7.6 ¾ , in), 6.69 (in) , 6.41 (within 加), 6.03 (within 加), 5.59 (within), 3.85 (eg), 3.09 (111, within), 2.87 (111, within), 2.63 (111, within), 2.53 (111, within) , 2.37 (111, within), 2.31 (111, within), 2.23 (example), 2.13 -
1.20（111, 1 1.20 (111, 1
<실시예 36> 2-（（5 -클로로- 2-（（4-（4-（（ /· 2/750-5 -하이드록시아다만탄- 2- 일）피페라진-:!-일）- 2 -메특시페닐）아미노）-피리미딘- 4 -일）아미노）-·/ ^3- 다이메틸벤즈아마이드의 제조 （화합물 36）
Figure imgf000089_0001
<Example 36> 2-((5-chloro-2-((4-(4-((/· 2/750-5-hydroxyadamantane-2-yl)piperazin-:!-yl)) - 2-Methoxyphenyl)amino)-pyrimidin- 4-yl)amino)-·/ ^3- Preparation of dimethylbenzamide (Compound 36)
Figure imgf000089_0001
［단계 1] 2-（（2, 5 -다이클로로피리미딘- 4 -일）아미노）- ᄊ 3 - 다이메틸벤즈아마이드의 제조 2021/111311 ?01/162020/061350
Figure imgf000090_0001
[Step 1] Preparation of 2-((2,5-dichloropyrimidin-4-yl)amino)-ᄊ 3-dimethylbenzamide 2021/111311 ?01/162020/061350
Figure imgf000090_0001
2 -아미노- 3 -다이메틸벤즈아마이드와 ¾狀03를 에탄올에 녹인 후 2,4,5- 트라이클로로피리미딘을 넣고 801에서 교반하였다. 반응 종결을 孔［：로 확인한 후 용매를 농축하고 생성된 고체를 아세트산 에틸에 녹여 증류수로 닦아냈다. 무수 황산 마그네슘으로 건조 후 여과하고 여 액을 농축한 후 아세토나이트릴 : 증류수 = 20: 1 로 재결정하여 표제 화합물을 얻었다. After dissolving 2-amino-3-dimethylbenzamide and ¾狀0 3 in ethanol, 2,4,5-trichloropyrimidine was added and stirred at 801. After confirming the completion of the reaction as 孔[:, the solvent was concentrated, the resulting solid was dissolved in ethyl acetate and washed with distilled water. After drying over anhydrous magnesium sulfate, filtration, and concentration of the filtrate, it was recrystallized from acetonitrile: distilled water = 20: 1 to obtain the title compound.
［단계 2］ 2-（（5 -클로로- 2-（（4-（4-（（ ＜ 5）-5 -하이드록시아다만탄- 2- 일）피페라진- 1 -일）- 2 -메톡시페닐）아미노）-피리미딘- 4 -일）아미노）- ᄊ 3- 다이메틸벤즈아마이드의 제조
Figure imgf000090_0002
[Step 2] 2-((5-chloro-2-((4-(4-((<5)-5-hydroxyadamantane-2-yl)piperazin-1-yl)-2-methyl Preparation of oxyphenyl)amino)-pyrimidin-4-yl)amino)- ᄊ 3-dimethylbenzamide
Figure imgf000090_0002
4-（4-（4 -아미노- 3 -메톡시페닐）피페라진- 1 -일）아다만탄- 1 -올과 상기 단계4-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)adamantan-1-ol and the above steps
1 에서 제조한 2-（（2, 5 -다이클로로피리미딘- 4 -일）아미노）- 3- 다이메틸벤즈아마이드를 2 -부탄올에 녹인 후 메탄설폰산을 넣고 1201에서 교반하였다. 반응 완료 후 반응 용액에 증류수를 가하고 아세트산 에틸로 추출하였다. 무수 황산 마그네슘으로 건조 후 여과하고 여액을 농축한 후 컬럼 크로마토그래피로 정제하여 표제 화합물을 얻었다. 2021/111311 ?01/162020/0613502-((2,5-dichloropyrimidin-4-yl)amino)-3-dimethylbenzamide prepared in 1 was dissolved in 2-butanol, methanesulfonic acid was added thereto, and the mixture was stirred at 1201. After completion of the reaction, distilled water was added to the reaction solution, followed by extraction with ethyl acetate. It was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain the title compound. 2021/111311 ?01/162020/061350
¾ » （400 ， 0[13）: 6 8.66 ， 페， 8.01 ， 페， 7.67 （111, 2 , 7.45 - 7.16 （111, 해）, 6.48 （111, 래）, 6.18 （111, 내）, 6.07 （加 내）, 3.81
Figure imgf000091_0001
예 ）, 3.09 （111, 태）, 2.87 （（!, I = 4.8 ¾ , 해）, 2.62 （111, 태）, 2.34 - 2.26 （111, 내 ）, 2.22 （ 예）, 2.14 - 1.98 （111, 태）, 1.83 - 1.61 （111, 해）, 1.42 - 1.24 （111, 예 ） ¾ » （400 ， 0[1 3 ]: 6 8.66 ， pe， 8.01 ， pe， 7.67 （111, 2 , 7.45 - 7.16 (111, year), 6.48 (111, lower), 6.18 (111, inner), 6.07 (within 加), 3.81
Figure imgf000091_0001
Example ), 3.09 (111, Tae), 2.87 ((!, I = 4.8 ¾ , year), 2.62 (111, Tae), 2.34 - 2.26 (111, In), 2.22 (Ex), 2.14 - 1.98 (111, Tae), 1.83 - 1.61 (111, year), 1.42 - 1.24 (111, yes)
<실시예 37> 메틸 （ /_2/25） ~4 -（ 4-（ 3 -메록시 -4 -（（ 4-（（ 2 -메틸 -6 -<Example 37> Methyl ( /_2/25) to 4 - ( 4- ( 3-meroxy -4 - ( ( 4- ( ( 2-methyl-6 -)
（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）페닐）피페라진-卜일）아다만테인-卜카복실례이트의 제조 （화합물 37）
Figure imgf000091_0002
Preparation of (methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-卜yl)adamantane-卜carboxylate (Compound 37)
Figure imgf000091_0002
[단계 1] 메틸 （仕 -4-（4-（4-（（4-클로로-5-[Step 1] Methyl （仕-4-（4-（4-（（4-chloro-5-
（트라이플루오로메틸）피리미딘- 2 -일）아미노）- 3 -메톡시페닐）피페라진- 1- 일）아다만테인- 1 -카복실례이트의 제조
Figure imgf000091_0003
2021/111311 ?01/162020/061350 실시 예 1 의 단계 3 에서 （ « - -（（간 -아미노- 3_ 메톡시페닐）아미노）아다만탄- 1 -올 대신에 메틸 （紅 ） -4-（4-（4 -아미노- 3- 메톡시페닐）피페라진- 1 -일）아다만테인- 1 -카복실례이트를 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . Preparation of (trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)adamantane-1-carboxylate
Figure imgf000091_0003
2021/111311 ?01/162020/061350 In step 3 of Example 1 ( « - - ((liver-amino-3_ methoxyphenyl) amino) methyl (紅) -4- ( The title compound was synthesized in the same manner as in Example 1 using 4-(4-amino-3-methoxyphenyl)piperazin-1-yl)adamantane-1-carboxylate.
[단계 2] 메틸 （紅 ）-4-（4-（3 -메톡시 - 4-（（4-（（2-메틸-6-[Step 2] Methyl (紅)-4-(4-(3-methoxy-4-((4-((2-methyl-6-)
（메틸카바모일）페닐）아미노）-5-（트라이플루오로메틸）피 리미딘-2- 일）아미노）페닐）피페라진- 1 -일）아다만테인- 1 -카복실레이트의 제조
Figure imgf000092_0001
Preparation of (methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)adamantane-1-carboxylate
Figure imgf000092_0001
（트라이플루오로메틸）피 리미딘- 2 -일）아미노）- 3 -메톡시페닐）아미노）아다만탄- 1 -올 대신에 메틸 （仕 -4-（4-（4-（（4 -클로로- 5-（트라이플루오로메틸）피 리미딘- 2- 일）아미노）- 3 -메톡시페닐）피페라진- 1 -일）아다만테인- 1 -카복실레이트를 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 .
Figure imgf000092_0002
0 ）이3）: 6 8.28 （ 111）， 8.26 （ 111）， 7.40 （（!， I =(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)adamantan-1-ol instead of methyl (仕-4-(4-(4-((4-) Chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)adamantane-1-carboxylate as in Example 1 The title compound was synthesized by this method.
Figure imgf000092_0002
0 ) is 3 ): 6 8.28 ( 111), 8.26 ( 111), 7.40 ((!, I =
7.3 ¾， 내）， 7.36 （（!， I = 7.5 ¾， 내）， 7.31 - 7.26 （111, 내）, 6.47 （（1, I = 2.0 ¾ , 페 , 6.15 - 5.95 （111, ¾）, 3.82
Figure imgf000092_0003
예）, 3.66
Figure imgf000092_0004
예）, 3.09 （111, , 2.847.3 ¾, within), 7.36 ((!, I = 7.5 ¾, within), 7.31 - 7.26 (111, within), 6.47 （（1, I = 2.0 ¾ , P , 6.15 - 5.95 （111, ¾）, 3.82
Figure imgf000092_0003
ex), 3.66
Figure imgf000092_0004
ex), 3.09 (111, , 2.84
（（1, I = 4.8 ¾ , 예）, 2.60 （111, 태）, 2.25 - 2.14 （111, 태）, 2.13 - 2.05 （111, 래）, 2.04 - 1.92 （111, 래）, 1.91 - 1.82 （111, 예）, 1.73 - 1.62 （111, 래）, 1.40 - 1.33 （111, 2021/111311 ?01/162020/061350 래) , 1.31 - 1.20 (111, ¾) ((1, I = 4.8 ¾ , eg), 2.60 (111, Tae), 2.25 - 2.14 (111, Tae), 2.13 - 2.05 (111, Ra), 2.04 - 1.92 (111, Ra), 1.91 - 1.82 ( 111, eg), 1.73 - 1.62 (111, lower), 1.40 - 1.33 (111, 2021/111311 ?01/162020/061350 Ra) , 1.31 - 1.20 (111, ¾)
<실시예 38> 메틸 0/ 5）-4-（4-（3 -메톡시- ^（^-（（요-메틸내-메틸카바모일ᅵ페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일 ）아미노）페닐）피페라진-!-일）아다만테인- 1 -카복실레이트의 제조 （화합물 38）
Figure imgf000093_0001
<Example 38> Methyl 0/5)-4-(4-(3-methoxy-^(^-((yo-methyl-methylcarbamoyl-phenyl)amino)-5-(trifluoromethyl) Preparation of pyrimidin-2-yl)amino)phenyl)piperazin-!-yl)adamantane-1-carboxylate (Compound 38)
Figure imgf000093_0001
［단계 1] 메틸 ( 5)-4-(4-(4-( (4 -클로로- 5-[Step 1] Methyl (5)-4-(4-(4-((4-chloro-5-)
（트라이플루오로메틸）피 리미딘- 2 -일）아미노）- 3 -메톡시페닐）피페라진- 1- 일）아다만테인- 1 -카복실례이트의 제조
Figure imgf000093_0002
실시 예 1 의 단계 3 에서 （ « - -（（간 -아미노- 3_ 메톡시페 닐）아미노）아다만탄- 1 -올 대신에 메틸 （ 5）-4-（4-（4 -아미노- 3- 메톡시페 닐）피페라진- 1 -일）아다만테인- 1 -카복실례이트를 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . Preparation of (trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)adamantane-1-carboxylate
Figure imgf000093_0002
In step 3 of Example 1 ( «--((liver-amino-3_ methoxyphenyl)amino)adamantan-1-ol instead of methyl ( 5 )-4-(4-(4-amino-3) The title compound was synthesized in the same manner as in Example 1 using -methoxyphenyl)piperazin-1-yl)adamantane-1-carboxylate.
［단계 2］ 메틸 （ ）-4-（4-（3-메톡시 -4-（（4-（（2-메틸-6- 2021/111311 ?01/162020/061350[Step 2] Methyl ( )-4-(4-(3-methoxy-4-((4-((2-methyl-6-) 2021/111311 ?01/162020/061350
（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피 리미딘- 2- 일）아미노）페닐）피페라진- 1 -일）아다만테인- 1 -카복실레이트의 제조
Figure imgf000094_0001
Preparation of (methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)adamantane-1-carboxylate
Figure imgf000094_0001
（트라이플루오로메틸）피 리미딘- 2 -일）아미노）- 3 -메톡시페닐）아미노）아다만탄- 1 -올 대신에 메틸 （ ）-4-（4-（4-（（4 -클로로- 5-（트라이플루오로메틸）피 리미딘- 2- 일）아미노）- 3 -메톡시페닐）피페라진- 1 -일）아다만테인- 1 -카복실레이트를 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 .
Figure imgf000094_0002
0 ）이3）: 6 8.27 （ 1¾， 8.26 （ 111）， 7.41 （（!， I =(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)adamantan-1-ol instead of methyl ( )-4-(4-(4-((4-) Chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)adamantane-1-carboxylate as in Example 1 The title compound was synthesized by this method.
Figure imgf000094_0002
0 ) is 3 ): 6 8.27 ( 1¾, 8.26 ( 111), 7.41 ((!, I =
7.3 ¾， 내）， 7.37 （（!， I = 7.5 ¾， 내）， 7.31 - 7.26 （111, 내）, 6.47 （（1, I = 2.07.3 ¾, within), 7.37 ((!, I = 7.5 ¾, within), 7.31 - 7.26 (111, within), 6.47 ((1, I = 2.0)
¾ , 페 , 6.15 - 5.95 （111, ¾）, 3.82 （ 예）, 3.66 （ 예）, 3.09 （111, , 2.84¾ , pe , 6.15 - 5.95 (111, ¾), 3.82 (example), 3.66 (example), 3.09 (111, , 2.84)
（（!, / = 4.8 ¾ , 예）, 2.60 （111, 태）, 2.28 - 2.13 （111, 해）, 2.07 （111, 내）, 1.98 （111, 내）, 1.90 - 1.77 （111, 태）, 1.75 - 1.48 （111, 611） ((!, / = 4.8 ¾ , e.g.), 2.60 (111, Tae), 2.28 - 2.13 (111, Year), 2.07 (111, In), 1.98 (111, In), 1.90 - 1.77 (111, Tae) , 1.75 - 1.48 (111, 611)
<실시예 39> （ ^/*2/25） 4（ 4-（ 3 -메특시 -4 -（（ 4-（（ 2 -메틸 -6 -<Example 39> ( ^/ * 2/25) 4 ( 4- ( 3-methyl-6 -
（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）페닐）피페라진- 1 -일）아다만테인- 1 -카복실산의 제조（화합물 39） 2021/111311 ?01/162020/061350
Figure imgf000095_0001
Preparation of (methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)adamantane-1-carboxylic acid (Compound 39) 2021/111311 ?01/162020/061350
Figure imgf000095_0001
［단계 1] （紅 5）-4-（4-（3 -메톡시 -4-（（4-（（2 -메틸- 6-[Step 1] (紅 5)-4-(4-(3-methoxy-4-((4-((2-methyl-6-)
（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피 리미딘- 2- 일）아미노）페닐）피페라진- 1 -일）아다만테인- 1 -카복실산의 제조
Figure imgf000095_0002
실시 예 17 의 단계 1 에서 4-（3 -메톡시 - 4-（（4-（（2 -메틸- 6-Preparation of (methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)adamantane-1-carboxylic acid
Figure imgf000095_0002
In step 1 of Example 17, 4-(3-methoxy-4-((4-((2-methyl-6-
（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피 리미딘- 2- 일）아미노）페녹시）아다만테인- 1 -카복실산 메틸 대신에 메틸 { trans）-A-{A-{?l - 메톡시 -4-（（4-（（2 -메틸- 6-（메틸카바모일）페닐）아미노）- 5- （트라이플루오로메틸）피 리미딘- 2 -일）아미노）페닐）피페라진- 1 -일）아다만테인- 1- 카복실례이트을 사용하여 실시 예 17 과 동일한 방법으로 표제 화합물을 합성하였다 . (methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenoxy)adamantane-1-carboxylate methyl instead of methyl { trans)-A-{A -{? l -methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pipe The title compound was synthesized in the same manner as in Example 17 using Razin-1-yl)adamantane-1-carboxylate.
¾ » （400 , 0）301））: 6 8.20
Figure imgf000095_0003
페 , 7.48 - 7.32 （111, 해）, 6.56 （（!, I = 2.4 내）, 6.12 （111, 래）, 3.83 （ 예）, 3.13 （111, 태）, 2.79 （ 예）, 2.71¾ » (400 , 0) 3 01)): 6 8.20
Figure imgf000095_0003
P, 7.48 - 7.32 (111, year), 6.56 ((!, I = within 2.4), 6.12 (111, lower), 3.83 (example), 3.13 (111, Tae), 2.79 (example), 2.71
（111, 태）, 2.30 - 2.22 （111, 예）, 2.21 （ 예）, 2.15 - 2.08 （111, 래）, 2.06 - 1.99 2021/111311 ?01/162020/061350(111, Tae), 2.30 - 2.22 (111, Yes), 2.21 (Yes), 2.15 - 2.08 (111, Rae), 2.06 - 1.99 2021/111311 ?01/162020/061350
(111, 래) , 1.96 - 1.84 (111, 해) , 1.48 - 1.40 (111, ¾) (111, Rae) , 1.96 - 1.84 (111, Year) , 1.48 - 1.40 (111, ¾)
<실시예 40> （ 5）-4-（4-（3 -메톡시- ^（（^（ -메틸서-메틸카바모일ᅵ페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일 ）아미노）페닐）피페라진- 1 -일）아다만테인- 1 -카복실산의 제조 （화합물 40）
Figure imgf000096_0001
<Example 40> (5)-4-(4-(3-methoxy-^((^(-methylser-methylcarbamoylᅵphenyl)amino)-5-(trifluoromethyl)pyrimidine-2 -yl)amino)phenyl)piperazin-1-yl)adamantane-1-carboxylic acid (compound 40)
Figure imgf000096_0001
［단계 1] ( -4-(4-(3 -메톡시- 4-((4-((2 -메틸- 6-[Step 1] ( -4-(4-(3-methoxy-4-((4-((2-methyl-6-)
（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）페닐）피페라진- 1 -일）아다만테인- 1 -카복실산의 제조
Figure imgf000096_0002
-Preparation of (methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)adamantane-1-carboxylic acid
Figure imgf000096_0002
-
（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）페녹시）아다만테인- 1 -카복실산 메틸 대신에 메틸 （ 5）-4-（4-（3 -메톡시_(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenoxy)adamantane-1-carboxylate methyl (5)-4-(4- (3-methoxy_
4-（（4-（（2 -메틸- 6-（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘_ 2021/111311 ?01/162020/0613504-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine_ 2021/111311 ?01/162020/061350
2 -일）아미노）페닐）피페라진- 1 -일）아다만테인- 1 -카복실례이트을 사용하여 실시 예 17 과 동일한 방법으로 표제 화합물을 합성하였다 . The title compound was synthesized in the same manner as in Example 17 using 2-yl)amino)phenyl)piperazin-1-yl)adamantane-1-carboxylate.
¾ » （400 , 0）301））: 6 8.21
Figure imgf000097_0001
페 , 7.49 - 7.33 （111, 해）, 6.57 （（!, I = 2.4 ¾ , 내）, 6.13 （111, 래）, 3.84 （ 예）, 3.14 （111, 태）, 2.80 （ 예）, 2.72 （111, 태）, 2.31 - 2.23 （111, 예）, 2.22 （ 예）, 2.16 - 2.09 （111, 래）, 2.07 - 2.00 （111, 래）, 1.97 - 1.85 （111, 해）, 1.49 - 1.41 （111, ¾） ¾ » (400 , 0) 3 01)): 6 8.21
Figure imgf000097_0001
P, 7.49 - 7.33 (111, year), 6.57 ((!, I = 2.4 ¾ , within), 6.13 (111, lower), 3.84 (example), 3.14 (111, Tae), 2.80 (example), 2.72 ( 111, Tae), 2.31 - 2.23 (111, Yes), 2.22 (Yes), 2.16 - 2.09 (111, Old), 2.07 - 2.00 (111, Old), 1.97 - 1.85 (111, Year), 1.49 - 1.41 ( 111, ¾)
<실시예 41> 4-（4-（3 -메톡시- ^（（^（（요-메틸대-메틸카바모일ᅵ페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）페닐）피페라진- 1 -일）- 메틸아다만테인- 1 -카복실사마이드의 제조<Example 41> 4-(4-(3-methoxy-^((^((yo-methyl to-methylcarbamoylᅵphenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl) )amino)phenyl)piperazin-1-yl)-methyladamantane-1-carboxyl samide
（화합물 41）
Figure imgf000097_0002
(Compound 41)
Figure imgf000097_0002
[단계 1] 4-（4-（3 -메톡시 - 4-（（4-（（2 -메틸- 6-（메틸카바모일）페닐）아미노）_[Step 1] 4-(4-(3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)_
5-（트라이플루오로메틸）피 리미딘- 2 -일）아미노）페닐）피페라진- 1 -일）- 1 메틸아다만테인- 1 -카복실사마이드의 제조 2021/111311 1^（:1^2020/061350
Figure imgf000098_0001
실시 예 18 의 단계 1 에서 4-（3 -메톡시- 4-（（4-（（2 -메틸- 6-Preparation of 5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)-1-methyladamantane-1-carboxyl amide 2021/111311 1^（:1^2020/061350
Figure imgf000098_0001
In step 1 of Example 18, 4-(3-methoxy-4-((4-((2-methyl-6-
（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）페녹시）아다만테인- 1 -카복실산 대신에 4-（4-（3 -메톡시- 4-（（4-（（2 -메틸_(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenoxy)adamantane-1-carboxylic acid instead of 4-(4-(3-methoxy-) 4-((4-((2-methyl_
6-（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）페닐）피페라진- 1 -일）아다만테인- 1 -카복실산을 사용하여 실시 예 18 과 동일한 방법으로 표제 화합물을 합성하였다.
Figure imgf000098_0002
6 8.19 （ 111）， 7.47 - 7.31 （111, 해）, 6.55 （（1,Example using 6-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)adamantane-1-carboxylic acid The title compound was synthesized in the same manner as in 18.
Figure imgf000098_0002
6 8.19 ( 111), 7.47 - 7.31 (111, year), 6.55 ( (1,
I = 2.4 ¾ , 내）, 6.11 （111, 래）, 3.82 （ 예）, 3.12 （111, 태）, 2.80 （ 예）, 2.78 （ 예）, 2.70 （111, ， 2.29 - 2.21 （111, 예）, 2.20 （ 예）, 2.14 - 2.07 （111, 2¾，I = 2.4 ¾ , within), 6.11 (111, lower), 3.82 (ex), 3.12 (111, tae), 2.80 (ex), 2.78 (ex), 2.70 (111, , 2.29 - 2.21 (111, ex) , 2.20 (eg), 2.14 - 2.07 (111, 2¾,
2.05 - 1.98 （111, 래）, 1.95 - 1.83 （111, 해）, 1.47 - 1.39 （111, ¾） 2.05 - 1.98 (111, year), 1.95 - 1.83 (111, year), 1.47 - 1.39 (111, ¾)
<실시예 42> 4-（4-（3 -메톡시- ^（^-（（요-메틸대-메틸카바모일ᅵ페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）페닐）피페라진-!-일）아다만테인- 1 -카복실사마이드의 제조 （화합물 42） 2021/111311 1^（:1^2020/061350
Figure imgf000099_0001
<Example 42> 4-(4-(3-methoxy-^(^-((yo-methyl to-methylcarbamoylᅵphenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl Preparation of )amino)phenyl)piperazin-!-yl)adamantane-1 -carboxyl amide (Compound 42) 2021/111311 1^（:1^2020/061350
Figure imgf000099_0001
[단계 1] 4-（4-（3 -메톡시- 4-（（4-（（2 -메틸- 6-（메틸카바모일）페닐）아미노）_[Step 1] 4-(4-(3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)_
5-（트라이플루오로메틸）피리미딘- 2 -일）아미노）페닐）피페라진- 1 -일）아다만테인- 1- 카복실사마이드의 제조
Figure imgf000099_0002
실시 예 41 의 단계 1 에서 메틸아민 염산염 대신에 암모늄 클로라이 1三 사용하여 실시 예 41 과 동일한 방법으로 표제 화합물을 합성하였다.
Figure imgf000099_0003
8 8.19 （ 111）， 7.47 - 7.31 （111, 해）, 6.55 （（1Preparation of 5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)adamantane-1-carboxylsamide
Figure imgf000099_0002
In step 1 of Example 41, the title compound was synthesized in the same manner as in Example 41, using ammonium chloride 1-3 instead of methylamine hydrochloride.
Figure imgf000099_0003
8 8.19 ( 111), 7.47 - 7.31 (111, year), 6.55 ((1)
/ = 2.4 ¾ , 내）, 6.11 （111, 래）, 3.82 （ 예）, 3.12 （111, 태）, 2.78 （ 예）, 2.70 （111, 태）, 2.29 - 2.21 （111, 예）, 2.20 （ 예）, 2.14 - 2.07 （111, 래）, 2.05 - 1.98/ = 2.4 ¾ , within), 6.11 (111, lower), 3.82 (ex), 3.12 (111, tae), 2.78 (ex), 2.70 (111, tae), 2.29 - 2.21 (111, eg), 2.20 ( ex), 2.14 - 2.07 (111, lower), 2.05 - 1.98
（111, 래）, 1.95 - 1.83 （111, 해）, 1.47 - 1.39 （111, ¾） (111, lower), 1.95 - 1.83 (111, year), 1.47 - 1.39 (111, ¾)
＜실시예 43> 4-（4-（3 -메특시 -4-（（4-（（2 -메틸- 6-<Example 43> 4-(4-(3-methyl-6-((4-((2-methyl-6-)
（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2 - 2021/111311 ?01/162020/061350 일）아미노）페닐）피페라진- 1 -일）-成 다이메틸아다만테인- 1 -카복실사마이드의 제조 （화합물 43）
Figure imgf000100_0001
(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-2 - 2021/111311 Preparation of 01/162020/061350 days)amino)phenyl)piperazin-1 -yl)-成 dimethyladamantane-1 -carboxyl samide (Compound 43)
Figure imgf000100_0001
[단계 1] 4-（4-（3 -메톡시- 4-（（4-（（2 -메틸- 6-（메틸카바모일）페닐）아미노）_ 5-（트라이플루오로메틸）피리미딘- 2 -일）아미노）페닐）피페라진- 1 -일）- ᄊ聲 아다만테인- 1 -카복실사마이드의 제조
Figure imgf000100_0002
실시 예 41 의 단계 1 에서 메틸아민 염산염 대신에 다이메틸아민 염산염을 사용하여 실시 예 41 과 동일한 방법으로 표제 화합물을 합성하였다.
Figure imgf000100_0003
6 8.19 ( 111)， 7.47 - 7.31 (111, 해) , 6.55 ((1,[Step 1] 4-(4-(3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino)_5-(trifluoromethyl)pyrimidine- Preparation of 2-yl)amino)phenyl)piperazin- 1-yl)- adamantane- 1 -carboxyl samide
Figure imgf000100_0002
The title compound was synthesized in the same manner as in Example 41 using dimethylamine hydrochloride instead of methylamine hydrochloride in step 1 of Example 41.
Figure imgf000100_0003
6 8.19 ( 111)， 7.47 - 7.31 (111, year) , 6.55 ((1,
/ = 2.4 1¾ ， 6.11 (111, 2¾， 3.82 ( 311)， 3.12 (111, 4¾， 2.98， ( 311)， 2.78 ， ， 2.70 (111, ， 2.29 - 2.21 (111, 예) , 2.20
Figure imgf000100_0004
예) , 2.14 - 2.07 (111, 2¾，/ = 2.4 1¾ , 6.11 (111, 2¾, 3.82 ( 311), 3.12 (111, 4¾, 2.98, ( 311), 2.78 , , 2.70 (111, , 2.29 - 2.21 (111, example) , 2.20)
Figure imgf000100_0004
ex) , 2.14 - 2.07 (111, 2¾，
2.05 - 1.98 (111, 래) , 1.95 - 1.83 (111, 해) , 1.47 - 1.39 (111, ¾) 2021/111311 ?01/162020/0613502.05 - 1.98 (111, year) , 1.95 - 1.83 (111, year) , 1.47 - 1.39 (111, ¾) 2021/111311 ?01/162020/061350
<실시예 44> 2-（（2-（（4-（4-（5 -아미노아다만탄- 2 -일）피페라진-!-일）- 2- 메톡시페닐）아미노）- 5-（트라이를루오로메틸）피리미딘- 4 -일）아미노）- 3- 다이메틸벤즈아마이드의 제조 （화합물 44）
Figure imgf000101_0001
<Example 44> 2-((2-((4-(4-(5-aminoadamantan-2-yl)piperazin-!-yl)-2-methoxyphenyl)amino)-5-( Preparation of trifluoromethyl)pyrimidin-4-yl)amino)-3-dimethylbenzamide (Compound 44)
Figure imgf000101_0001
［단계 1] （9 플루오렌 -9 -일）메틸 (4-(4-(4-( (4 -클로로- 5-[Step 1] (9 fluorene -9 -yl) methyl (4- (4- (4- ( (4-chloro-5 -
（트라이플루오로메틸）피 리미딘- 2 -일）아미노）- 3 -메톡시페닐）피페라진- 1- 일）아다만탄- 1 -일）카바메이트의 제조
Figure imgf000101_0002
실시 예 1 의 단계 3 에서 （ « - -（（간 -아미노- 3_ 메톡시페닐）아미노）아다만탄- 1 -올 대신에 （911-플루오렌 -9 -일）메틸 （4-（4-（4_ 아미노- 3 -메톡시페닐）피페라진- 1 -일）아다만탄- 1 -일）카바메이트를 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다 . Preparation of (trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)adamantan-1-yl)carbamate
Figure imgf000101_0002
In step 3 of Example 1, (911-fluoren-9-yl)methyl (4-(4- The title compound was synthesized in the same manner as in Example 1 using (4_amino-3-methoxyphenyl)piperazin-1-yl)adamantan-1-yl)carbamate.
［단계 2］ （9 플루오렌 -9 -일）메틸 （4-（4-（3 -메톡시 - 4-（（4-（（2 -메틸- 6-[Step 2] (9-fluoren-9-yl)methyl (4-(4-(3-methoxy-4-((4-((2-methyl-6-)
（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피 리미딘- 2- 일）아미노）페닐）피페라진- 1 -일）아다만탄- 1 -일）카바메이트의 제조 2021/111311 ?01/162020/061350
Figure imgf000102_0001
실시 예 1 의 단계 4 에서 （紅 5） -4-（（4-（（4 -클로로- 5-Preparation of (methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)adamantan-1-yl)carbamate 2021/111311 ?01/162020/061350
Figure imgf000102_0001
In step 4 of Example 1 (紅 5) -4- ((4- ((4-chloro-5-
（트라이플루오로메틸）피리미딘- 2 -일）아미노）- 3 -메톡시페닐）아미노）아다만탄- 1 -올 대신에 메틸 （仕 -4-（4-（4-（（4 -클로로- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）- 3 -메톡시페닐）피페라진- 1 -일）아다만테인- 1 -카복실레이트를 사용하여 실시 예 1 과 동일한 방법으로 표제 화합물을 합성하였다. (trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)amino)adamantan-1-ol instead of methyl (仕-4-(4-(4-((4-chloro) - 5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)adamantane-1-carboxylate in the same manner as in Example 1 The title compound was synthesized.
[단계 3] 2-（（2-（（4-（4-（5 -아미노아다만탄- 2 -일）피페라진- 1 -일）- 2- 메톡시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᄊ 3- 다이메틸벤즈아마이드의 제조
Figure imgf000102_0002
상기 단계 2 에서 제조한 （9 플루오렌 -9 -일）메틸 （4-（4-（3 -메톡시- 4-（（4- （（2 -메틸- 6-（메틸카바모일）페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 2- 일）아미노）페닐）피페라진- 1 -일）아다만탄- 1 -일）카바메이트를 아세토나이트릴에 녹인 후 106 냉각하였다. 다이에틸아민을 천천히 적가하였다. 01 에서 1 시간 교반한 후 상온에서 15 시간 교반하였다. 용매를 감압 농축하고 컬럼 크로마토그래피로 정제하여 표제 화합물을 얻었다. 2021/111311 ?01/162020/061350[Step 3] 2-((2-((4-(4-(5-aminoadamantan-2-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-(tri Preparation of fluoromethyl)pyrimidin-4-yl)amino)- ᄊ 3-dimethylbenzamide
Figure imgf000102_0002
(9-fluoren-9-yl)methyl (4-(4-(3-methoxy-4-((4-((2-methyl-6-(methylcarbamoyl)phenyl)amino) prepared in step 2) )-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)adamantan-1-yl)carbamate was dissolved in acetonitrile and cooled to 106 . Diethylamine was slowly added dropwise. After stirring at 01 for 1 hour, the mixture was stirred at room temperature for 15 hours. The solvent was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. 2021/111311 ?01/162020/061350
¾ » （400 , 0犯13）: 6 8.27 （
Figure imgf000103_0001
7.42 （（!， / = 7.3 ¾ ， 내）， 7.35 （（!， I = 7.5 ¾， 내）， 7.32 - 7.27 （111, 내）, 6.48 （（1, I = 2.0
Figure imgf000103_0002
내）, 6.10 （加 내）, 6.01 （ 내）, 3.83 （ 예）, 3.10 （111, 태）, 2.85 （（!, I = 4.8 예）, 2.62 （111, 태）, 2.34 - 2.26 （111, 내）, 2.22 （ 예）, 2.14 - 1.98 （111, 태）, 1.83 - 1.61 （111, 해）, 1.42 - 1.24 （111, 예） ¾ » （400 , 0犯1 3 ）: 6 8.27 （
Figure imgf000103_0001
7.42 （（!， / = 7.3 ¾ ， my）， 7.35 (（!， I = 7.5 ¾， my), 7.32 - 7.27 (111, my), 6.48 (（1, I = 2.0
Figure imgf000103_0002
within), 6.10 (within 加), 6.01 (within), 3.83 (ex.), 3.10 (111, Tae), 2.85 ((!, I = 4.8 ex), 2.62 (111, Tae), 2.34 - 2.26 (111, Inner), 2.22 (Example), 2.14 - 1.98 (111, Tae), 1.83 - 1.61 (111, Year), 1.42 - 1.24 (111, Yes)
<실시예 45> 2-（（2-（（4-（4-（5 -메틸아미노아다만탄- 2 -일）피페라진- 1 -일）- 2- 메특시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- 3- 다이메틸벤즈아마이드의 제조 （화합물 45）
Figure imgf000103_0003
<Example 45> 2-((2-((4-(4-(5-methylaminoadamantan-2-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5- Preparation of (trifluoromethyl)pyrimidin-4-yl)amino)-3-dimethylbenzamide (Compound 45)
Figure imgf000103_0003
[단계 1] 2-（（2-（（4-（4-（5 -메틸아미노아다만탄- 2 -일）피페라진- 1 -일）- 2- 메톡시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᄊ 3- 다이메틸벤즈아마이드의 제조
Figure imgf000103_0004
상기 실시예 44 에서 제조한 2-((2-((4-(4-(5-아미노아다만탄-2_ 일)피페라진- 1-일)- 2 -메톡시페닐)아미노)- 5-(트라이플루오로메틸)피리미딘- 4- 일)아미노)- ᄊ 3 -다이메틸벤즈아마이드를 클로로포름에 녹이고 포타슘 카보네이트를 가하여 교반하였다. 아이오도메테인을 1당량 천천히 가한후 상온에서 교반하였다. 용매를 감압 농축하고 컬럼 크로마토그래피로 정제하여 표제 화합물을 얻었다. [Step 1] 2-((2-((4-(4-(5-methylaminoadamantan-2-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-( Preparation of trifluoromethyl)pyrimidin-4-yl)amino)- ᄊ 3-dimethylbenzamide
Figure imgf000103_0004
2-((2-((4-(4-(5-aminoadamantan-2-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-prepared in Example 44 (trifluoromethyl)pyrimidin-4-yl)amino)-ᄊ 3-dimethylbenzamide was dissolved in chloroform, potassium carbonate was added thereto, and the mixture was stirred. After slowly adding 1 equivalent of iodomethane, the mixture was stirred at room temperature. The solvent was concentrated under reduced pressure and purified by column chromatography to obtain the title compound.
¾ NMR (400 MHz, CDCb): 6 8.27 (s, 2H, overlapped), 7.42 (d, J = 7.3 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.32 - 7.27 (m, 1H), 6.48 (d, J = 2.0 Hz, 1H), 6.10 (br s, 1H), 6.01 (s, 1H), 3.83 (s, 3H), 3.10 (m, 4H), 2.85 (d, J = 4.8 Hz, 3H), 2.62 (m, 4H), 2.55 (s, 3H), 2.34 - 2.26 (m, 1H), 2.22 (s, 3H), 2.14 - 1.98 (m, 4H), 1.83 - 1.61 (m, 5H), 1.42 - 1.24 (m, 3H) ¾ NMR (400 MHz, CDCb): 6 8.27 (s, 2H, overlapped), 7.42 (d, J = 7.3 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.32 - 7.27 (m, 1H) ), 6.48 (d, J = 2.0 Hz, 1H), 6.10 (br s, 1H), 6.01 (s, 1H), 3.83 (s, 3H), 3.10 (m, 4H), 2.85 (d, J = 4.8) Hz, 3H), 2.62 (m, 4H), 2.55 (s, 3H), 2.34 - 2.26 (m, 1H), 2.22 (s, 3H), 2.14 - 1.98 (m, 4H), 1.83 - 1.61 (m, 5H), 1.42 - 1.24 (m, 3H)
<실시예 46> 2-( (2-( (4-(4-(5 -다이메틸아미노아다만탄- 2 -일)피페라진- 1- 일 )-2 -메특시페닐)아미노)- 5- (트라이플루오로메틸)피리미딘- 4 -일)아미노)- ᆻ 3- 다이메틸벤즈아마이드의 제조 (화합물 46)
Figure imgf000104_0001
<Example 46> 2-((2-((4-(4-(5-dimethylaminoadamantan-2-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5 - (Trifluoromethyl) pyrimidin-4-yl) amino) - ᆻ Preparation of 3-dimethylbenzamide (Compound 46)
Figure imgf000104_0001
[단계 1] 2-( (2-( (4-(4-(5 -다이메틸아미노아다만탄- 2 -일)피페라진- 1 -일)_ 2 -메톡시페닐)아미노)- 5-(트라이플루오로메틸)피리미딘- 4 -일)아미노)- ᄊ 3 - \¥02021/111311 1»(：17182020/061350 다이메틸벤즈아마이드의 제조
Figure imgf000105_0001
상기 실시예 44 에서 제조한 2-((2-((4-(4-(5-아미노아다만탄-2_ 일)피페라진- 1-일)- 2 -메톡시페닐)아미노)- 5-(트라이플루오로메틸)피리미딘- 4- 일)아미노)- ᄊ 3 -다이메틸벤즈아마이드를 클로로포름에 녹이고 포타슘 카보네이트를 가하여 교반하였다. 아이오도메테인 (2 equiv.)을 천천히 가한 후 상온에서 교반하였다. 용매를 감압 농축하고 컬럼 크로마토그래피로 정제하여 표제 화합물을 얻었다. [Step 1] 2-((2-((4-(4-(5-dimethylaminoadamantan-2-yl)piperazin-1-yl)_2-methoxyphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)amino)- ᄊ 3 - \¥02021/111311 1»(：17182020/061350 Preparation of dimethylbenzamide
Figure imgf000105_0001
2-((2-((4-(4-(5-aminoadamantan-2-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-prepared in Example 44 (trifluoromethyl)pyrimidin-4-yl)amino)-ᄊ 3-dimethylbenzamide was dissolved in chloroform, potassium carbonate was added thereto, and the mixture was stirred. Iodomethane (2 equiv.) was slowly added thereto, followed by stirring at room temperature. The solvent was concentrated under reduced pressure and purified by column chromatography to obtain the title compound.
¾ NMR (400 MHz, CDCb): 6 8.27 (s, 2H, overlapped), 7.42 (d, J = 7.3 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.32 - 7.27 (m, 1H), 6.48 (d, J = 2.0 Hz, 1H), 6.10 (br s, 1H), 6.01 (s, 1H), 3.83 (s, 3H), 3.10 (m, 4H), 2.85 (d, J = 4.8 Hz, 3H), 2.62 (m, 4H), 2.34 - 2.26 (m, 1H), 2.24 (s, 6H), 2.22 (s, 3H), 2.14 - 1.98 (m, 4H), 1.83 - 1.61 (m, 5H), 1.42 - 1.24 (m, 3H) ¾ NMR (400 MHz, CDCb): 6 8.27 (s, 2H, overlapped), 7.42 (d, J = 7.3 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.32 - 7.27 (m, 1H) ), 6.48 (d, J = 2.0 Hz, 1H), 6.10 (br s, 1H), 6.01 (s, 1H), 3.83 (s, 3H), 3.10 (m, 4H), 2.85 (d, J = 4.8) Hz, 3H), 2.62 (m, 4H), 2.34 - 2.26 (m, 1H), 2.24 (s, 6H), 2.22 (s, 3H), 2.14 - 1.98 (m, 4H), 1.83 - 1.61 (m, 5H), 1.42 - 1.24 (m, 3H)
<실시예 47> 2-( (2-( (4-(4-(5 -아크릴아마이도아다만탄- 2 -일)피페라진- 1- 일 )-2 -메특시페닐)아미노)- 5- (트라이플루오로메틸)피리미딘- 4 -일)아미노)- ᆻ 3- 다이메틸벤즈아마이드의 제조 (화합물 47) 2021/111311 1^(:1^ 2020/061350
Figure imgf000106_0001
<Example 47> 2-((2-((4-(4-(5-acrylamidoadamantan-2-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5- Preparation of (trifluoromethyl)pyrimidin-4-yl)amino)-ᆻ3-dimethylbenzamide (Compound 47) 2021/111311 1^(:1^ 2020/061350
Figure imgf000106_0001
[단계 1] 2-（（2-（（4-（4-（5 -아크릴아마이도아다만탄- 2 -일）피페라진- 1 -일）- 2 -메톡시페닐）아미노）- 5-（트라이플루오로메틸）피리미딘- 4 -일）아미노）- ᄊ 3 - 다이메틸벤즈아마이드의 제조
Figure imgf000106_0002
상기 실시 예 44 에서 제조한 2-((2-((4-(4-(5-아미노아다만탄-2- 일)피페라진- 1-일)- 2 -메톡시페닐)아미노)- 5-(트라이플루오로메틸)피리미딘- 4- 일)아미노)- ᄊ 3 -다이메틸벤즈아마이드를 클로로포름에 녹이고 포타슘 카보네이트를 가하여 교반하였다. 아크릴로일 클로라이드를 천천히 가한후상온에서 교반하였다. 용매를 감압 농축하고 컬럼 크로마토그래피로 정제하여 표제 화합물을 얻었다. [Step 1] 2-((2-((4-(4-(5-acrylamidoadamantan-2-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-( Preparation of trifluoromethyl)pyrimidin-4-yl)amino)- ᄊ 3-dimethylbenzamide
Figure imgf000106_0002
2-((2-((4-(4-(5-aminoadamantan-2-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5 prepared in Example 44 -(trifluoromethyl)pyrimidin-4-yl)amino)- ᄊ 3-dimethylbenzamide was dissolved in chloroform, potassium carbonate was added thereto, and the mixture was stirred. After slowly adding acryloyl chloride, the mixture was stirred at room temperature. The solvent was concentrated under reduced pressure and purified by column chromatography to obtain the title compound.
¾ NMR (400 MHz, CDCb): 6 8.27 (s, 2H, overlapped), 7.42 (d, J = 7.3 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.32 - 7.27 (m, 1H), 6.52 (m, 1H), 6.48 (d, J = 2.0 Hz, 1H), 6.10 (br s, 1H), 6.06 (m, 1H), 6.01 (s, 1H), 5.74 (m, 1H), 3.83 (s, 3H), 3.10 (m, 4H), 2.85 (d, J = 4.8 Hz, 3H), 2.62 (m, 4H), 2.34 - 2.26 (m, 1H), 2.22 (s, 3H), 2.14 - 1.98 (m, 4H), 1.83 - 1.61 (m, 5H), 1.42 - 1.24 (111, 예) 시험예 ¾ NMR (400 MHz, CDCb): 6 8.27 (s, 2H, overlapped), 7.42 (d, J = 7.3 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.32 - 7.27 (m, 1H) ), 6.52 (m, 1H), 6.48 (d, J = 2.0 Hz, 1H), 6.10 (br s, 1H), 6.06 (m, 1H), 6.01 (s, 1H), 5.74 (m, 1H), 3.83 (s, 3H), 3.10 (m, 4H), 2.85 (d, J = 4.8 Hz, 3H), 2.62 (m, 4H), 2.34 - 2.26 (m, 1H), 2.22 (s, 3H), 2.14 - 1.98 (m, 4H), 1.83 - 1.61 (m, 5H), 1.42 - 1.24 (111, yes) test example
＜실험예 1 ñ 화합물의 FAK, Pyk2 및 InsR 저해 활성 측정 본 발명의 아다만탄 (Adamantane) 유도체 화합물들의 FAK, Pyk2 및 InsR 에 대한 저해 활성은 생화학적 키나제 분석을 통해 확인한 것으로， 하기 표 1 은 각 화합물의 각 키나제 저해 활성에 대한 IC5o 값을 표기한 것이다. 간략히 설명하면， 키나제 시험은 Pr omega사의 각 키나제를 포함하는 ADP-G 1 oä Kinase Assay Kit (FAK, Pr omega, V1971 ; Pyk2, Pr omega, M083 ; InsR, Pr omega, V9401)을 사용하여， 본 발명의 아다만탄 유도체 화합물을 처리 후 제조사의 설명에 따라 수행 및 정량하였다. <Experimental Example 1 - Measurement of FAK, Pyk2 and InsR inhibitory activity of compound The inhibitory activity on FAK, Pyk2 and InsR of the adamantane derivative compounds of the present invention was confirmed through biochemical kinase analysis, Table 1 below IC 5 o values for each kinase inhibitory activity of each compound are indicated. Briefly, the kinase test was performed using the ADP-G 1 oä Kinase Assay Kit (FAK, Pro omega, V1971; Pyk2, Pro mega, M083; InsR, Pro mega, V9401) containing each kinase of Pro mega. After treatment, the adamantane derivative compound of the invention was performed and quantified according to the manufacturer's instructions.
【표 1]
Figure imgf000107_0001
Figure imgf000108_0005
상기 표 1 을 참조하면， 본 발명에 따른 아다만탄 유도체는 FAK 및 Pyk2(FAK2)에 대한 저해 활성이 우수함을 알 수 있었다. 아울러， FAK 및 Pyk2(FAK2)의 활성을 선택적으로 저해하면서 인슐린 수용체 (insul in receptor , Ins- 묘) 활성은 저해하지 않는 것을 알 수 있었다. 【Table 1】
Figure imgf000107_0001
Figure imgf000108_0005
Referring to Table 1, it can be seen that the adamantane derivative according to the present invention has excellent inhibitory activity against FAK and Pyk2 (FAK2). In addition, it was found that while selectively inhibiting the activity of FAK and Pyk2 (FAK2), the insulin receptor (insul in receptor, Ins-myo) activity was not inhibited.
<실험예 2> 화합물의 인간 삼중음성유방암 세포주인 쇼-쌔-231에서의
Figure imgf000108_0001
저해 활성 측정 본 발명의 아다만탄 유도체 화합물들의 생체 외
Figure imgf000108_0002
대한 저해 활성을 측정하기 위해， 인간 삼중음성유방암 세포주인 1 -16-231을 대상으로
Figure imgf000108_0003
효소결합면역흡착검사 시험을 수행한 것으로 하기 표 2는 각 화합물의 1050 값을 나타낸 것이다. 간략히 설명하면， 6 -웰 플레이트의 각 웰에 1산06의
Figure imgf000108_0004
세포를 분주 후 세포의 안정화를 24 시간 유도하고， 1 시간 동안 각 화합물을 상이한 농도 (0， 1 , 5, 10, 50, 100, 500, lOOOnM)로 처리 후 FAK (Phospho) [pY397] Human ELISA Kit (Thermo Fisher Scient i f ic, KH00441)을 사용하여 제조사의 설명에 따라 효소결합면역흡착검사 시험을 수행하였다 . <Experimental Example 2> Compounds in human triple-negative breast cancer cell line show-sae-231
Figure imgf000108_0001
Inhibitory activity measurement of the adamantane derivative compounds of the present invention in vitro
Figure imgf000108_0002
In order to measure the inhibitory activity against, the human triple-negative breast cancer cell line 1 -16-231 was
Figure imgf000108_0003
The enzyme-linked immunosorbent test was performed, and Table 2 below shows the 10 50 values of each compound. Briefly, 1 acid 0 6 in each well of a 6-well plate
Figure imgf000108_0004
After dividing the cells, the stabilization of the cells was induced for 24 hours, and each compound was treated with different concentrations (0, 1 , 5, 10, 50, 100, 500, lOOOnM) for 1 hour and then FAK (Phospho) [pY397] Human ELISA The enzyme-linked immunosorbent assay was performed using the kit (Thermo Fisher Scient if ic, KH00441) according to the manufacturer's instructions.
【표 2]
Figure imgf000109_0004
상기 표 2 를 참조하면， 본 발명에 따른 아다만탄 유도체는 인간
Figure imgf000109_0001
활성이 우수함을 알 수 있었다. 【Table 2】
Figure imgf000109_0004
Referring to Table 2, the adamantane derivative according to the present invention is a human
Figure imgf000109_0001
It was found that the activity was excellent.
＜실험예 3 ñ 다양한 인간 삼중음성유방암 세포주에서의
Figure imgf000109_0002
측정 본 발명의 아다만탄 유도체 화합물인 화합물 4 의
Figure imgf000109_0003
대한 저해 활성은 다양한 삼중음성유방암 세포주에서 상기 설명된 바와 같이 FAK比 397] 효소결합면역흡착검사를 통해 확인되었고， 하기 표 3 은 각 세포주에 대한 1^0 값을 나타낸 것이다. <Experimental Example 3 - In various human triple-negative breast cancer cell lines
Figure imgf000109_0002
Measurement of compound 4, which is an adamantane derivative compound of the present invention
Figure imgf000109_0003
inhibition of The activity was confirmed through the enzyme-linked immunosorbent assay [FAK比397] as described above in various triple-negative breast cancer cell lines, and Table 3 below shows the values of 1^0 for each cell line.
【표 3]
Figure imgf000110_0002
본 발명 화합물 4 의 여러 키나제에 대한 저해 활성 능력은 다음과 같다. 본 키나제 활성 저해 자료는 Eurofins회사의 kinase screening 및 profiling결과에서 산출된 것으로， 하기 표 4는 화합물의 단일 농도 (lyM)에서 107 가지의 스크리닝 된 키나제 중 70% 이상 저해하는 해당 키나제들의 저해 활성 정도 (% 억제율) 및 이들에 대한 IC5o값을 나타낸 것이다. 【Table 3】
Figure imgf000110_0002
The inhibitory activity ability of compound 4 of the present invention against various kinases is as follows. This kinase activity inhibition data is calculated from the results of kinase screening and profiling of Eurofins Company, and Table 4 below shows the inhibitory activity degree of the kinases inhibiting 70% or more among 107 screened kinases at a single concentration (lyM) of the compound ( % inhibition) and IC 5 o values for them.
【표 4]
Figure imgf000110_0003
상기 표 3 을 참조하면， 본 발명에 따른 아다만탄 유도체는 다양한 삼중음성유방암 세포주인 1 8-231， 1 8-453， 11070， _20， _549 및
Figure imgf000110_0001
활성이 우수함을 알 수 있었다. <실험예 4> 다양한 인간 삼중음성유방암 세포주에서의 성장 저해 활성 측정 암 세포의 3 차원 (3D) 배양 조건에서의 성장을 측정하기 위한 방법은 3D spheroid assay를 수행하였다. 간략히 설명하면， 96 -웰 플랫 플레이트의 각 웰에 5xl03 의 삼중음성유방암 세포를 MammoCultä Human Medium Kit (Stemcel l Technologies , #05620)을 사용하여 3 일 동안 3 차원 배양하였고 형성된 암 세포 구상체에 상이한 농도 (0， 0.2， 0.5， 1 , 2, 5, 10, 20 u M)의 화합물 4를 96 시간 동안 처리하였다. 화합물의 암 세포 성장 저해 효과는 Cel lTiter-Glo® 3D Cel l Viabi l ity Assay Kit(Pr omega, G9681)을 사용하여 제조사의 설명에 따라 정량하였다. 도 1 은 3D spheroid assay 의 대표 예로 MDA-MB-231 세포에서 상이한 농도의 화합물 처리에 의한 암 세포 구상체의 성장 저해 정도를 나타낸 것이다. 하기 표 5 는 MDA-MB-231 을 포함한 다양한 삼중음성유방암 세포주에서의 본 발명의 아다만탄 유도체 화합물인 화합물 4 에 대한 암 세포 구상체 성장 저해 활성을 ICso 값으로 나타낸 것이다. 【Table 4】
Figure imgf000110_0003
Referring to Table 3, adamantane derivatives according to the present invention are various triple-negative breast cancer cell lines 1 8-231, 1 8-453, 11070, _20, _549 and
Figure imgf000110_0001
It was found that the activity was excellent. <Experimental Example 4> Measurement of growth inhibitory activity in various human triple-negative breast cancer cell lines A 3D spheroid assay was performed as a method for measuring the growth of cancer cells in three-dimensional (3D) culture conditions. Briefly, in each well of a 96-well flat plate, 5xl0 3 triple-negative breast cancer cells were three-dimensionally cultured for 3 days using the MammoCultä Human Medium Kit (Stemcell Technologies, #05620). Concentrations (0, 0.2, 0.5, 1, 2, 5, 10, 20 u M) of compound 4 were treated for 96 hours. The cancer cell growth inhibitory effect of the compound was quantified using Cel Titer-Glo® 3D Cel Viabi lity Assay Kit (Pr omega, G9681) according to the manufacturer's instructions. 1 shows the degree of inhibition of growth of cancer cell spheroids by treatment with different concentrations of compounds in MDA-MB-231 cells as a representative example of 3D spheroid assay. Table 5 below shows the cancer cell spheroid growth inhibitory activity of Compound 4, an adamantane derivative compound of the present invention, in various triple-negative breast cancer cell lines including MDA-MB-231 as ICso values.
【표 5]
Figure imgf000111_0001
도 1 을 참조하면， 본 발명에 따른 아다만탄 유도체는 모든 농도에서 암 세포 구상체 저해 활성이 우수함을 알 수 있었다. 또한， 상기 표 5 를 참조하면， 본 발명에 따른 아다만탄 유도체는 다양한 삼중음성유방암 세포주인 1 231， 쇼 - 16-453 , 11070， _20， _549 및 ¾5781에서의 암 세포 구상체 성장 저해 활성이 우수함을 알 수 있었다. [Table 5]
Figure imgf000111_0001
Referring to FIG. 1 , it was found that the adamantane derivative according to the present invention had excellent cancer cell spheroid inhibitory activity at all concentrations. In addition, referring to Table 5, adamantane derivatives according to the present invention are various triple-negative breast cancer cell lines 1 231, show- It was found that 16-453, 11070, _20, _549 and ¾5781 cancer cell spheroid growth inhibitory activity was excellent.
<실험예 5 ñ 인간 삼중음성유방암 세포주인 MDA-MB-231에서의 3D 침윤 저해 효과 세포의 침윤 분석은 3D 침윤 분석법에 따라 수행하고 정량 하였다. 간략히 설명하면， MDA-MB-231 세포를 96 -웰 라운드 플레이트（5xl03/웰）에 3일 동안 배양하여 암 세포 구상체를 형성 후 반 고형인 매트리겔과 타입 I 콜라겐의 혼합에 고정하여 상이한 농도（1， 5 u M）의 화합물 4를 처리하였다. 침윤 정도는 72시간 후 현미경（도 2 참조） 및 이미징 소프트웨어인 ImageJ를 사용하여 분석한 면적 값을 하기 공식（식 1）에 의거하여 정량 및 그래프로 나타내었다（도 3 참조）. <Experimental Example 5 - Invasion analysis of 3D invasion inhibitory effect cells in the human triple-negative breast cancer cell line MDA-MB-231 was performed and quantified according to the 3D invasion assay. Briefly, MDA-MB-231 cells were cultured in a 96-well round plate (5xl0 3 /well) for 3 days to form cancer cell spheroids, and then fixed in a mixture of semi-solid Matrigel and type I collagen. A concentration of (1, 5 u M) of compound 4 was treated. The degree of infiltration was expressed as quantitative and graphed values based on the following formula (Equation 1), analyzed using a microscope (see Fig. 2) and imaging software, ImageJ, after 72 hours (see Fig. 3).
[식 1] 침윤율 （relative invasion） = （화합물 처리군의 총 면적 -화합물 처리군의 구상체 면적）/（대조군의 총 면적 -대조군의 구상체 면적） 도 2 및 3 을 참조하면， 본 발명에 따른 아다만탄 유도체는 인간 삼중음성유방암 세포주인 MDA-MB-231 에서의 침윤 저해 활성이 우수함을 알 수 있었다. [Equation 1] Infiltration rate (relative invasion) = (total area of compound treated group - spheroid area of compound treated group) / (total area of control - spheroid area of control group) Referring to FIGS. 2 and 3, the present invention It was found that the adamantane derivative according to the present invention has excellent invasion inhibitory activity in the human triple-negative breast cancer cell line, MDA-MB-231.
<실험예 6 ñ 삼중음성유방암 이종이식 마우스 모델 （xenograft mouse model）에서의 종양 성장 저해 효과 <Experimental Example 6 - Tumor growth inhibitory effect in triple-negative breast cancer xenograft mouse model
5주령 수컷
Figure imgf000112_0001
순응 1주일 후， 1산06의 10/ -231 세포를 마우스에 피하 접종하여 14 일 후인 종양의 부피가 약 100^13을 형성할 때까지 관찰하였다. 삼중음성유방암 이종이식 마우스 모델에서의 도출된 후보물질의 종양 성장 저해 효과를 확인하기 위해， 그룹 당 8 마리를 포함시켜 대조군（¥삵101）， 3 군의 상이 농도의 실험군들 （4-201 /1¾， 4-401 /1¾ 및 4-801 /1¾）로 분류하여 각 화합물을 매일 1 회 처치하였다. 마우스의 종양 부피는 격일로 1 주일에 3 회 측정하였고， 마우스는 세포 접종 후 29 일째에 희생하였다. 도 4 는 하기 공식（식 2）에 의거하여 산출한 종양 부피를 약물 처지 시작일을 1 일로하여 그래프로 나타낸 것이다. 5 weeks old male
Figure imgf000112_0001
After 1 week of acclimatization, 10/ -231 cells of 0 6 After subcutaneous inoculation into mice, 14 days later, the tumor volume was observed until it formed about 100^1 3 . In order to confirm the tumor growth inhibitory effect of the derived candidate substance in the triple-negative breast cancer xenograft mouse model, 8 mice per group were included in the control group (¥ 101), and the experimental groups with different concentrations of 3 groups (4-201 / 1¾, 4-401 /1¾ and 4-801 /1¾), and each compound was treated once daily. The tumor volume of the mice was measured 3 times a week on every other day, and the mice were sacrificed on the 29th day after cell inoculation. 4 is a graph showing the tumor volume calculated based on the following formula (Equation 2), with the starting date of drug treatment as 1 day.
[식 2] 종양 부피 （빼3） = [（종양 단경 2 X 종양 장경）/ 2] 하기 표 6 은 대조군 평균 종양성장 대비 각 화합물 처치 그룹의 평균 종양성장의 비교를 하기 공식（식 3）에 의거하여
Figure imgf000113_0001
산출하여 나타낸 것이다. [Equation 2] Tumor volume (minus 3 ) = [(Tumor minor diameter 2 X Tumor major diameter)/2] Table 6 below shows the comparison of the average tumor growth of each compound treatment group compared to the average tumor growth of the control group in the following formula (Formula 3) based on
Figure imgf000113_0001
calculated and shown.
[식 3] [Equation 3]
%TGI = 100 X [1- (TVf inal treated- TV init ial treated)/ (TVf inal control- TV initial control ) 1 %TGI = 100 X [1- (TV f inal treated- TV i nit ial treated )/ (TV f inal control- TV i nitial control ) 1
【표 6]
Figure imgf000113_0002
도 4 및 표 6 을 참조하면， 본 발명에 따른 아다만탄 유도체는 삼중음성유방암 이종이식 마우스 모델에서의 종양 성장 저해 활성이 우수함을 알 수 2021/111311 ?01/162020/061350 있었다. 상기 실험예 1 내지 6의 결과들로부터， 본 발명에 따른 아다만탄 유도체는 관련 질환의 치료 효과가 우수함을 알 수 있었다. 상기에서는 본 발명의 바람직한 실시예를 참조하여 설명하였지만， 해당 기술 분야의 숙련된 당업자는 하기의 특허 청구 범위에 기재된 본 발명의 사상 및 영역으로부터 벗어나지 않는 범위 내에서 본 발명을 다양하게 수정 및 변경시킬 수 있음을 이해할 수 있을 것이다. 【Table 6】
Figure imgf000113_0002
4 and Table 6, it can be seen that the adamantane derivative according to the present invention has excellent tumor growth inhibitory activity in a triple-negative breast cancer xenograft mouse model. There was 2021/111311 ?01/162020/061350. From the results of Experimental Examples 1 to 6, it was found that the adamantane derivative according to the present invention has an excellent therapeutic effect on related diseases. Although the above has been described with reference to the preferred embodiment of the present invention, those skilled in the art can variously modify and change the present invention within the scope without departing from the spirit and scope of the present invention described in the claims below. You will understand that you can.

Claims

2021/111311 ?01/162020/061350 【특허청구범위】 【청구항 1] 하기 화학식 1로 나타내는 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물: 2021/111311 - 01/162020/061350 [Claim] [Claim 1] An adamantane derivative represented by the following formula (1), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof:
[화학식 1]
Figure imgf000115_0001
상기 화학식 1에서， 및 는 각각 독립적으로 단결합， -1()알킬렌， -1()알케닐렌， 02- 10알키닐렌， (1¾) -， -〔:(=0) (1¾) -， (1¾)-〔:(=0) -， -0(=0)-, -0 -, -0(=0)-0 -, - 1¾0-〔:(=0)-0 -， (1¾)-3(=0) -， (1¾)-3(=0)2 -， - =0)(= -1¾) - 또는 - 이고; [Formula 1]
Figure imgf000115_0001
In the general formula (1), and are each independently a single bond, - 1 () alkylene, - 1 () alkenylene, 0 2-10 alkynylene, (1¾) -, - [: (= 0) (1¾) - ， (1¾)-[:(=0) -， -0(=0)-, -0 -, -0(=0)-0 -, - 1¾0-[:(=0)-0 -, (1¾ ) -3 (= 0) -, (1¾) -3 (= 0) 2 -, - = 0) (= -1¾) - or -;
¾ 및 ¾는 각각독립적으로 -1()헤테로사이클로알킬렌， ¾-1()사이클로알킬렌， -16아릴렌 또는 04,헤테로아릴렌이고; ¾ and ¾ are each independently a - 1 () hetero cycloalkylene, ¾- 1 () cycloalkylene, 16 or 04 arylene, and heteroarylene;
1¾는 II， -1()알킬， 02 - 1()알케닐， -0^3, =0, - -1¾， - ■0:=0) 크 또는 01- 10헤테로사이클로알킬이고， 묘4는 -0-1¾이고; 1¾ is II, - 1 () alkyl, 0 2 - 1 () alkenyl, -0 ^ 3, = 0, - -1¾, - ■ 0: = 0) or greater than 0 and 1-10 heterocycloalkyl, seedlings 4 is -0-1¾;
¾ 및 ¾은 각각 독립적으로 II또는 -10알킬이고; 묘7는 _0?3 또는 할로겐 원자이고; 2021/111311 ?01/162020/061350
Figure imgf000116_0001
킬이고 ; II， I) 및 (1 는 각각 독립적으로 0 또는 1 이다. ¾ and ¾ are each independently II or -10 alkyl; Myo 7 is _ 0-3 or a halogen atom; 2021/111311 ?01/162020/061350
Figure imgf000116_0001
kill; II, I) and (1 are each independently 0 or 1.
【청구항 2] 제 1항에 있어서 상기 화학식 1에서
Figure imgf000116_0002
(： 및 (1는 각각 독립적으로 1 , 2 또는 3인， 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물 . 2021/111311 1^(:1^2020/061350 [Claim 2] The method according to claim 1, wherein in Formula 1,
Figure imgf000116_0002
(: and (1 is each independently 1, 2 or 3, adamantane derivatives, pharmaceutically acceptable salts thereof, stereoisomers thereof, hydrates or solvates thereof. 2021/111311 1^(:1^2020/061350
【청구항 3] 제 1항에 있어서， 상기 화학식 1에서，
Figure imgf000117_0001
아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물. [Claim 3] The method according to claim 1, wherein in Formula 1,
Figure imgf000117_0001
Adamantane derivatives, pharmaceutically acceptable salts thereof, stereoisomers thereof, hydrates or solvates thereof.
【청구항 4] 제 1항에 있어서， 상기 화학식 1로 나타내는 화합물은 하기 화학식 2로 나타내는 화합물인， 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물: [Claim 4] The compound of claim 1, wherein the compound represented by Formula 1 is a compound represented by Formula 2 below, an adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or solvate thereof:
[화학식 2] 2021/111311 ?01/162020/061350
Figure imgf000118_0001
此 II， I) 및 (1는 각각 독립적으로 0 또는 1이다. [Formula 2] 2021/111311 ?01/162020/061350
Figure imgf000118_0001
此 II, I) and (1 are each independently 0 or 1.
【청구항 5］ 제 1항에 있어서 2021/111311 ?01/162020/061350 상기 화학식 1로 나타내는 화합물은 하기 표에 나타낸 화합물들로 이루어진 군으로부터 선택된 어느 하나인， 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물:
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
[Claim 5] According to claim 1, 2021/111311 - 01/162020/061350 The compound represented by Formula 1 is any one selected from the group consisting of compounds shown in the following table, adamantane derivatives, pharmaceutically acceptable salts thereof, stereoisomers thereof, hydrates thereof or solvates:
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
2021/111311 ?01/162020/061350
Figure imgf000127_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
2021/111311 ?01/162020/061350
Figure imgf000127_0001
【청구항 6] 제 1항 내지 제 5항 중 어느 한 항에 따른 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 입체 이성질체， 이의 수화물 또는 용매화물을 유효성분으로 포함하는， 약학적 조성물 . 2021/111311 ?01/162020/061350 [Claim 6] A pharmaceutical composition comprising the adamantane derivative according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof as an active ingredient. . 2021/111311 ?01/162020/061350
【청구항 7] 제 6항에 있어서， 상기 약학적 조성물은
Figure imgf000128_0001
활성 관련 질환의 예방 또는 치료용인 것인， 약학적 조성물 . [Claim 7] The method of claim 6, wherein the pharmaceutical composition is
Figure imgf000128_0001
For the prevention or treatment of activity-related diseases, the pharmaceutical composition.
【청구항 8] 제 7항에 있어서， 상기
Figure imgf000128_0002
관련 질환은， 위암， 폐암， 간암， 대장암， 소장암， 췌장암， 뇌암， 뼈암， 흑색종， 유방암， 자궁암， 자궁경부암， 난소암， 두경부암， 갑상선암， 부갑상선암， 신장암， 전립선암， 요도암， 방광암， 중피종 등을 포함한 고형암과 백혈병， 다발성골수종， 림프종을 포함하는 혈액암으로 이루어진 군으로부터 선택되는 적어도 하나인 것인， 약학적 조성물 . [Claim 8] The method according to claim 7, wherein the
Figure imgf000128_0002
Related diseases are stomach cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, uterine cancer, cervical cancer, ovarian cancer, head and neck cancer, thyroid cancer, parathyroid cancer, kidney cancer, prostate cancer, urethra cancer The pharmaceutical composition which is at least one selected from the group consisting of solid cancer including cancer, bladder cancer, mesothelioma, and leukemia, multiple myeloma, and blood cancer including lymphoma.
【청구항 9] 제 6항에 있어서， 상기 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물은
Figure imgf000128_0003
적어도 어느 하나의 키나제를 억제하는 것인， 약학적 조성물 . 2021/111311 ?01/162020/061350 [Claim 9] The method according to claim 6, wherein the adamantane derivative, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof
Figure imgf000128_0003
Inhibiting at least one kinase, the pharmaceutical composition. 2021/111311 ?01/162020/061350
【청구항 10】 제 1항 내지 제 5항 중 어느 한 항에 따른 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물의 치료학적으로 유효한 양을 개체에 투여하는 단계를 포함하는，
Figure imgf000129_0001
활성 관련 질환의 예방 또는 치료 방법 . [Claim 10] A therapeutically effective amount of the adamantane derivative according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof is administered to an individual. comprising steps;
Figure imgf000129_0001
A method of preventing or treating an activity-related disease.
【청구항 11】 관련 질환의 예방 또는 치료를 위한 제 1항 내지 제 5항 중 어느 한 항에 따른 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물의 용도 . [Claim 11] Use of the adamantane derivative according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvate thereof for the prevention or treatment of a related disease.
【청구항 12】 관련 질환의 예방 또는 치료용 약제의 제조를 위한 제 1항 내지 제 5항 중 어느 한 항에 따른 아다만탄 유도체， 이의 약학적으로 허용 가능한 염， 이의 입체 이성질체， 이의 수화물 또는 용매화물의 용도 . [Claim 12] The adamantane derivative according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate or a solvent thereof for the preparation of a medicament for the prevention or treatment of related diseases. Use of cargo.
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